Indole compounds as positive allosteric modulators of the muscarinic receptor

ABSTRACT

In one aspect, the invention relates to indole compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 1  (mAChR M 1 ); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/356,741, filed Jun. 21, 2010, which is hereby incorporatedby reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with U.S. Government support under grant numbersMH082867, MH084659 and MH073676 awarded by the National Institute ofHealth and the National Institute of Mental Health (NIMH). The U.S.government has certain rights in the invention.

BACKGROUND

Cholinergic neurotransmission involves the activation of nictonicacetylcholine receptors (nAChRs) or the muscarinic acetylcholinereceptors (mAChRs) by the binding of the endogenous orthosteric agonistacetylcholine (ACh). Conditions associated with cognitive impairment,such as Alzheimer's disease, are accompanied by a reduction ofacetylcholine content in the brain. This is believed to be the result ofdegeneration of cholinergic neurons of the basal forebrain, which widelyinnervate multiple areas of the brain, including the associationcortices and hippocampus, that are critically involved in higherprocesses. Clinical data supports that cholinergic hypofunctioncontributes to the cognitive deficits of patients suffering fromschizophrenia. Efforts to increase acetylcholine levels have focused onincreasing levels of choline, the precursor for acetylcholine synthesis,and on blocking acetylcholineesterase (AChE), the enzyme thatmetabolizes acetylcholine. As a result, acetylcholinesterase (AChE)inhibitors, which inhibit the hydrolysis of ACh, have been approved inthe United States for use in the palliative, but not disease-modifying,treatment of the cognitive deficits in AD patients.

Attempts to augment central cholinergic function through theadministration of choline or phosphatidylcholine have not beensuccessful. AChE inhibitors have shown therapeutic efficacy, but havebeen found to have frequent cholinergic side effects due to peripheralacetylcholine stimulation, including abdominal cramps, nausea, vomiting,and diarrhoea. These gastrointestinal side effects have been observed inabout a third of the patients treated. In addition, some AChEinhibitors, such as tacrine, have also been found to cause significanthepatotoxicity with elevated liver transaminases observed in about 30%of patients. The adverse effects of AChE inhibitors have severelylimited their clinical utility. An alternative approach topharmacologically target cholinergic hypofunction is the activation ofmAChRs, which are widely expressed throughout the body.

The mAChRs are members of the family A GPCRs and include five subtypes,designated M₁-M₅. The M₁, M₃ and M₅ subtypes mainly couple to G_(q) andactivate phospholipase C, whereas the M₂ and M₄ subtypes mainly coupleto G_(i/o) and associated effector systems. These five distinct mAChRsubtypes have been identified in the mammalian central nervous systemwhere they are prevalent and differentially expressed. M₁-M₅ havevarying roles in cognitive, sensory, motor and autonomic functions.Thus, without wishing to be bound by a particular theory, it is believedthat selective agonists of mAChR subtypes that regulate processesinvolved in cognitive function could prove superior to be superiortherapeutics for treatment of psychosis, schizophrenia and relateddisorders. The muscarinic M₄ receptor has been shown to have a majorrole in cognitive processing and is believed to have a major role in thepathophysiology of psychotic disorders, including schizophrenia.

Evidence suggests that the most prominent adverse effects of AChEinhibitors and other cholinergic agents are mediated by activation ofperipheral M₂ and M₃ mAChRs and include bradycardia, GI distress,excessive salivation, and sweating. In contrast, M₄ has been viewed asthe most likely subtype for mediating the effects of muscarinicacetylcholine receptor dysfunction in psychotic disorders, includingschizophrenia, cognition disorders, and neuropathic pain. Because ofthis, considerable effort has been focused on developing selective M₁agonists for treatment of these disorders. Unfortunately, these effortshave been largely unsuccessful because of an inability to developcompounds that are highly selective for the mAChR M₁. Because of this,mAChR agonists that have been tested in clinical studies induce a rangeadverse effects by activation of peripheral mAChRs. To fully understandthe physiological roles of individual mAChR subtypes and to furtherexplore the therapeutic utility of mAChR ligands in psychosis, includingschizophrenia, cognition disorders and other disorders, it can beimportant to develop compounds that are highly selective activators ofmAChR M₁ and other individual mAChR subtypes.

Previous attempts to develop agonists that are highly selective forindividual mAChR subtypes have failed because of the high conservationof the orthosteric ACh binding site. To circumvent problems associatedwith targeting the highly conserved orthosteric ACh binding site, it isbelieved that developing compounds that act at allosteric sites onmAChRs that are removed from the orthosteric site and are lesshighly-conserved. This approach is proving to be highly successful indeveloping selective ligands for multiple GPCR subtypes. In the case ofmAChRs, a major goal has been to develop allosteric ligands thatselectively increase activity of mAChR M₁ or other mAChR subtypes.Allosteric activators can include allosteric agonists, that act at asite removed from the orthosteric site to directly activate the receptorin the absence of ACh as well as positive allosteric modulators (PAMs),which do not activate the receptor directly but potentiate activation ofthe receptor by the endogenous othosteric agonist ACh. Also, it ispossible for a single molecule to have both allosteric potentiator andallosteric agonist activity.

Recently, muscarinic agonists including xanomeline have been shown to beactive in animal models with similar profiles to known antipsychoticdrugs, but without causing catalepsy (Bymaster et al., Eur. J.Pharmacol. 1998, 356, 109, Bymaster et al., Life Sci. 1999, 64, 527;Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901; Shannon et al.,Schizophrenia Res. 2000, 42, 249.). Further, xanomeline was shown toreduce psychotic behavioral symptoms such as delusions, suspiciousness,vocal outbursts, and hallucinations in Alzheimer's disease patients(Bodick et al., Arch. Neurol. 1997, 54, 465.), however treatment inducedside effects, e.g., gastrointestinal effects, have severely limited theclinical utility of this compound.

Despite advances in muscarinic acetylcholine receptor research, there isstill a scarcity of compounds that are both potent, efficacious, andselective activators of the AChR M₁ and also effective in the treatmentof neurological and psychiatric disorders associated with cholinergicactivity and diseases in which the acetylcholine muscarinic M₁ receptoris involved. These needs and other needs are satisfied by the presentinvention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tosubstituted indole analogues useful as positive allosteric modulators(i.e., potentiators) of the muscarinic acetylcholine receptor M₁ (mAChRM₁), methods of making same, pharmaceutical compositions comprisingsame, and methods of treating neurological and psychiatric disordersassociated with muscarinic acetylcholine receptor dysfunction usingsame.

Disclosed are compounds represented by formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are compounds represented by formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are methods of making and using the compounds, forexample to allosterically modulate or activate the muscarinic receptoror treat a disorder associated with the muscarinic receptor in a cell orsubject, such as a mammal.

Also disclosed are synthetic method comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R² is selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; and wherein R⁸ is selected fromhydrogen, optionally substituted alkyl, optionally substituted alkaryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl, and (b) reacting with a compound having astructure represented by the formula:

wherein R³ comprises two substituents independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein Z is —O—, —S—, or —NA¹-;wherein R⁴ is selected from hydrogen, a hydrolysable residue, andoptionally substituted alkyl; wherein A¹ is selected from optionallysubstituted alkyl, optionally substituted alkaryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and(c) optionally oxidizing, thereby providing a compound having astructure represented by the formula:

wherein n is 0, 1, or 2.

Also disclosed are synthetic method comprising the steps of: (a)providing a compound having a structure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R² is selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; and wherein R⁹ is selected fromhydrogen and a moiety having a structure represented by the formula:

wherein R³ comprises two substituents independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein Z is —O—, —S—, or —NA¹-;wherein A¹ is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; and wherein nis 0, 1, or 2, b) optional deprotonation, and c) reaction with A²X,wherein X is a leaving group, thereby providing a compound having astructure represented by the formula:

wherein A² is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl.

Also disclosed are the products of the disclosed methods.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a product of a disclosed syntheticmethod and a pharmaceutically acceptable carrier.

Also disclosed are methods for the manufacture of a medicament toactivate the mAChR M₁ in a mammal comprising combining at least onedisclosed compound or at least one disclosed product with apharmaceutically acceptable carrier or diluent.

Also disclosed are uses of a disclosed compound or a disclosed productin the manufacture of a medicament for the treatment of a disorderassociated with muscarinic acetylcholine receptor dysfunction in amammal.

Disclosed are methods for the treatment of a neurological and/orpsychiatric disorder associated with muscarinic acetylcholine receptordysfunction in a mammal comprising the step of administering to themammal a therapeutically effective amount of least one compound having astructure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for potentiation of muscarinic acetylcholinereceptor activity in a mammal comprising the step of administering tothe mammal a therapeutically effective amount of least one compoundhaving a structure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for partial agonism of muscarinicacetylcholine receptor activity in a mammal comprising the step ofadministering to the mammal a therapeutically effective amount of leastone compound having a structure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for modulating muscarinic acetylcholinereceptor activity in a mammal comprising the step of administering tothe mammal an effective amount of least one compound having a structurerepresented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are methods for modulating muscarinic acetylcholinereceptor activity in at least one cell, comprising the step ofcontacting the at least one cell with an effective amount of least onecompound having a structure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are uses of a compound having a structure represented bya formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and an effective amount of acompound represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

Also disclosed are kits comprising at least one compound having astructure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof, and one or more of: a. at least one agent known to increasemAChR M₁ activity; b. at least one agent known to decrease mAChR M₁activity; c. at least one agent known to treat a disorder associatedwith cholinergic activity; d. instructions for treating a disorderassociated with cholinergic activity; e. instructions for treating adisorder associated with M₁ receptor activity; or f. instructions foradministering the compound in connection with cognitive or behavioraltherapy.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canrequire independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature.

When one or more stereochemical features are present, Cahn-Ingold-Prelogrules for stereochemistry can be employed to designate stereochemicalpriority, E/Z specification, and the like. One of skill in the art canreadily ascertain the structure of a compound If given a name, either bysystemic reduction of the compound structure using naming conventions,or by commercially available software, such as CHEMDRAW™ (CambridgesoftCorporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or can not occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the terms “mAChR M₁,” “cholinergic receptor, muscarinic1,” and “muscarinic acetylcholine M₁ receptor” can be usedinterchangeably and refer to a GPCR encoded by the CHRM1 gene, which hasa human gene map locus of 11q12-q13, and described by Entrez Genecytogenetic band: 11q13; Ensembl cytogenetic band: 11q12.3; and HGNCcytogenetic band: 11q12-q13. The term mAChR M₁ refers to a nativeprotein that has 460 amino acids with an unglycosylated molecular weightof about 51,421 Da. The term refers The term mAChR M₁ is inclusive ofthe splice isoforms or variants, and also is inclusive of suchalternative designations as: cholinergic receptor, muscarinic 1; M1R;M1; HM1; muscarinic acetylcholine receptor M1; and MGC301252 as used bythose skilled in the art to that protein encoded by human gene CHRM1 orthe non-human ortholog or homolog thereof.

As used herein, the term “orthosteric site” refers to the primarybinding site on a receptor that is recognized by the endogenous ligandor agonist for that receptor. For example, the orthosteric site in themAChR M₁ receptor is the site that acetylcholine binds.

As used herein, the term “mAChR M₁ receptor positive allostericmodulator” refers to any exogenously administered compound or agent thatdirectly or indirectly augments the activity of mAChR M₁ receptor in thepresence or in the absence of acetylcholine in an animal, in particulara mammal, for example a human. In one aspect, a mAChR M₁ receptorpositive allosteric modulator increases the activity of the mAChR M₁receptor in a cell in the presence of extracellular acetylcholine. Thecell can be Chinese hamster ovary (CHO-K1) cells transfected with humanmAChR M₁. The cell can be Chinese hamster ovary (CHO-K1) cellstransfected with rat mAChR M₁ receptor. The cell can be Chinese hamsterovary (CHO-K1) cells transfected with a mammalian mAChR M₁. The term“mAChR M₁ receptor positive allosteric modulator” includes a compoundthat is a “mAChR M₁ receptor allosteric potentiator” or a “mAChR M₁receptor allosteric agonist,” as well as a compound that has mixedactivity comprising pharmacology of both an “mAChR M₁ receptorallosteric potentiator” and an “mAChR M₁ receptor allosteric agonist”.The term “mAChR M₁ receptor positive allosteric modulator also includesa compound that is a “mAChR M₁ receptor allosteric enhancer.”

As used herein, the term “mAChR M₁ receptor allosteric potentiator”refers to any exogenously administered compound or agent that directlyor indirectly augments the response produced by the endogenous ligand(such as acetylcholine) when the endogenous ligand binds to theorthosteric site of the mAChR M₁ receptor in an animal, in particular amammal, for example a human. The mAChR M₁ receptor allostericpotentiator binds to a site other than the orthosteric site, that is, anallosteric site, and positively augments the response of the receptor toan agonist or the endogenous ligand. In one aspect, an allostericpotentiator does not induce desensitization of the receptor, activity ofa compound as an mAChR M₁ receptor allosteric potentiator providesadvantages over the use of a pure mAChR M₁ receptor orthosteric agonist.Such advantages can include, for example, increased safety margin,higher tolerability, diminished potential for abuse, and reducedtoxicity.

As used herein, the term “mAChR M₁ receptor allosteric enhancer” refersto any exogenously administered compound or agent that directly orindirectly augments the response produced by the endogenous ligand (suchas acetylcholine) in an animal, in particular a mammal, for example ahuman. In one aspect, the allosteric enhancer increases the affinity ofthe natural ligand or agonist for the orthosteric site. In anotheraspect, an allosteric enhancer increases the agonist efficacy. The mAChRM₁ receptor allosteric potentiator binds to a site other than theorthosteric site, that is, an allosteric site, and positively augmentsthe response of the receptor to an agonist or the endogenous ligand. Anallosteric enhancer has no effect on the receptor by itself and requiresthe presence of an agonist or the natural ligand to realize a receptoreffect.

As used herein, the term “mAChR M₁ receptor allosteric agonist” refersto any exogenously administered compound or agent that directly augmentsthe activity of the mAChR M₁ receptor in the absence of the endogenousligand (such as acetylcholine) in an animal, in particular a mammal, forexample a human. The mAChR M₁ receptor allosteric agonist binds to asite that is distinct from the orthosteric acetylcholine site of themAChR M₁ receptor and influences the binding of an agonist or thenatural ligand to the orthosteric site of the mAChR M₁ receptor. Becauseit does not require the presence of the endogenous ligand, activity of acompound as an mAChR M₁ receptor allosteric agonist provides advantagesover the use of a pure mAChR M₁ receptor allosteric potentiator, such asmore rapid onset of action.

As used herein, the term “mAChR M₁ receptor neutral allosteric ligand”refers to any exogenously administered compound or agent that binds toan allosteric site without affecting the binding or function of agonistsor the natural ligand at the orthosteric site in an animal, inparticular a mammal, for example a human. However, a neutral allostericligand can block the action of other allosteric modulators that act viathe same site.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects. In some aspects of the disclosedmethods, the subject has been diagnosed with a need for treatment of oneor more neurological and/or psychiatric disorder associated withmuscarinic acetylcholine receptor dysfunction prior to the administeringstep. In some aspects of the disclosed method, the subject has beendiagnosed with a need for positive allosteric modulation of muscarinicacetylcholine receptor activity prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with aneed for partial agonism of muscarinic acetylcholine receptor activityprior to the administering step. In some aspects of the disclosedmethod, the subject has been diagnosed with a psychotic disorder, e.g.schizophrenia, a cognitive disorder, or neuropathic pain prior to theadministering step. In some aspects of the disclosed method, the subjecthas been identified with a disorder treatable by activation of the mAChRM₁ receptor and/or or a need for activation/agonism of mAChR M₁ activityprior to the administering step. In some aspects of the disclosedmethod, the subject has been identified with anxiety or a relateddisorder prior to the administering step. In one aspect, a subject canbe treated prophylactically with a compound or composition disclosedherein, as discussed herein elsewhere.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein. For example,“diagnosed with a disorder treatable by modulation of mAChR M₁” meanshaving been subjected to a physical examination by a person of skill,for example, a physician, and found to have a condition that can bediagnosed or treated by a compound or composition that can modulatemAChR M₁. As a further example, “diagnosed with a need for modulation ofmAChR M₁” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditioncharacterized by mAChR M₁ activity. Such a diagnosis can be in referenceto a disorder, such as a neurodegenerative disease, and the like, asdiscussed herein. For example, the term “diagnosed with a need forpositive allosteric modulation of muscarinic acetylcholine receptoractivity” refers to having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by positive allosteric modulation ofmuscarinic acetylcholine receptor activity. For example, “diagnosed witha need for partial agonism of muscarinic acetylcholine receptoractivity” means having been subjected to a physical examination by aperson of skill, for example, a physician, and found to have a conditionthat can be diagnosed or treated by partial agonism of muscarinicacetylcholine receptor activity. For example, “diagnosed with a need fortreatment of one or more neurological and/or psychiatric disorderassociated with acetylcholine dysfunction” means having been subjectedto a physical examination by a person of skill, for example, aphysician, and found to have one or more neurological and/or psychiatricdisorder associated with acetycholine dysfunction.

As used herein, the phrase “identified to be in need of treatment for adisorder,” or the like, refers to selection of a subject based upon needfor treatment of the disorder. For example, a subject can be identifiedas having a need for treatment of a disorder (e.g., a disorder relatedto mAChR M₁ activity) based upon an earlier diagnosis by a person ofskill and thereafter subjected to treatment for the disorder. It iscontemplated that the identification can, in one aspect, be performed bya person different from the person making the diagnosis. It is alsocontemplated, in a further aspect, that the administration can beperformed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

The term “contacting” as used herein refers to bringing a disclosedcompound and a cell, target muscarinic acetylcholine receptor, or otherbiological entity together in such a manner that the compound can affectthe activity of the target (e.g., spliceosome, cell, etc.), eitherdirectly; i.e., by interacting with the target itself, or indirectly;i.e., by interacting with another molecule, co-factor, factor, orprotein on which the activity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side affects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response. In a yetfurther aspect, the response is in vitro. In a still further aspect, theresponse is in Chinese hamster ovary (CHO-K1) cell transfected withhuman mAChR M₁. In a yet further aspect, the response is a Chinesehamster ovary (CHO-K1) cell transfected with rat mAChR M₁. In an evenfurther aspect, the response is in a Chinese hamster ovary (CHO-K1) celltransfected with a mammalian mAChR M₁.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance. In a yet further aspect, theinhibition is measured in vitro. In a still further aspect, theinhibition is measured in a Chinese hamster ovary (CHO-K1) celltransfected with human mAChR M₁. In a yet further aspect, the inhibitionis measured in a Chinese hamster ovary (CHO-K1) cell transfected withrat mAChR M₁. In an even further aspect, the inhibition is measured in aChinese hamster ovary (CHO-K1) cell transfected with a mammalian mAChRM₁.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkylgroup can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula (CH₂)_(a)—, where “a” is an integer of from 2to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² orOA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiolas described herein. The term “biaryl” is a specific type of aryl groupand is included in the definition of “aryl.” Biaryl refers to two arylgroups that are bound together via a fused ring structure, as innaphthalene, or are attached via one or more carbon-carbon bonds, as inbiphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500.“Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The term “halide” as used herein refers to the halogens fluorine,chlorine, bromine, and iodine.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, triazine, including 1,2,4-triazine and1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine,piperidine, piperazine, morpholine, azetidine, tetrahydropyran,tetrahydrofuran, dioxane, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O—(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o))₂; —N(R^(o))N(R^(o)C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR^(o)₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o), —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o) ₂; SiR^(o) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, brosylate, and halides.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable minor images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Inglod-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

When the disclosed compounds contain one chiral center, the compoundsexist in two enantiomeric forms. Unless specifically stated to thecontrary, a disclosed compound includes both enantiomers and mixtures ofenantiomers, such as the specific 50:50 mixture referred to as a racemicmixture. The enantiomers can be resolved by methods known to thoseskilled in the art, such as formation of diastereoisomeric salts whichmay be separated, for example, by crystallization (see, CRC Handbook ofOptical Resolutions via Diastereomeric Salt Formation by David Kozma(CRC Press, 2001)); formation of diastereoisomeric derivatives orcomplexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step can liberate the desired enantiomeric form. Alternatively,specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designatedenantiomeric form of the compounds can be provided in enantiomericexcess (ee). Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%, for example, greater than60%, greater than 70%, greater than 75%, greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 98%, or greaterthan 99%. In one aspect, the designated enantiomer is substantially freefrom the other enantiomer. For example, the “R” forms of the compoundscan be substantially free from the “S” forms of the compounds and are,thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms ofthe compounds can be substantially free of “R” forms of the compoundsand are, thus, in enantiomeric excess of the “R” forms.

When a disclosed compound has two or more chiral carbons, it can havemore than two optical isomers and can exist in diastereoisomeric forms.For example, when there are two chiral carbons, the compound can have upto four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and(R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are minorimage stereoisomers of one another. The stereoisomers that are notminor-images (e.g., (S,S) and (R,S)) are diastereomers. Thediastereoisomeric pairs can be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Unless otherwise specifically excluded, a disclosedcompound includes each diastereoisomer of such compounds and mixturesthereof.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labelled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvate orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. Unless stated to the contrary, theinvention includes all such possible tautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

The following abbreviations are used herein. AcOEt: ethyl acetate. AcOH:acetic acid. ACN: acetonitrile. BuOH: 1-butanol. DIPEA or DIEA:diisopropylethylamine. DMAP: 4-dimethylaminopyridine. DCM:dichloromethane. DCE: 1,2-dichloroethane. DIPE: diisopropylether. DIPEA:N,N-diisopropylethylamine. DMF: N,N-dimethyl formamide. DMSO:dimethylsulfoxide. EDC: 1-ethyl-3-[3-dimethylaminopropyl]carbodiimidehydrochloride. EtOAc: ethyl acetate. EtOH: ethanol. h: Hours. HPLC:high-performance liquid chromatography. HOBt: 1-hydroxybenzotriazole.iPrOH: 2-propanol. LC-MS or LCMS: liquid chromatography/massspectrometry. [M+H]+: protonated mass of the free base of the compound.M.p.: melting point. MeCN: Acetonitrile. MeOH: methanol. Min: Minutes.NMR: nuclear magnetic resonance. RP: reversed phase. Rt: retention time(in minutes). RT: Room temperature. TEA: triethylamine. THF:tetrahydrofuran. TMEDA: N,N,N′,N′-tetramethylethylenediamine.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds can not be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Compounds

In one aspect, the invention relates to compounds useful as positiveallosteric modulators of the muscarinic acetylcholine receptor M₁ (mAChRM₁). More specifically, in one aspect, the present invention relates tocompounds that allosterically modulate mAChR M₁ receptor activity,affecting the sensitivity of mAChR M₁ receptors to agonists withoutacting as orthosteric agonists themselves. The compounds can, in oneaspect, exhibit subtype selectivity.

In one aspect, the disclosed compounds exhibit positive allostericmodulation of mAChR M₁ response to acetylcholine as an increase inresponse to non-maximal concentrations of acetylcholine in Chinesehamster ovary (CHO-K1) cells transfected with rat mAChR M₁ in thepresence of the compound, compared to the response to acetylcholine inthe absence of the compound. In further aspect, the Chinese hamsterovary (CHO-K1) cells are transfected with human mAChR M₁. In yet afurther aspect, Chinese hamster ovary (CHO-K1) cells are transfectedwith mAChR M₁ of a mammal.

In one aspect, the compounds of the invention are useful in thetreatment neurological and psychiatric disorders associated withmuscarinic acetylcholine receptor dysfunction and other diseases inwhich muscarinic acetylcholine receptors are involved, as furtherdescribed herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, the invention relates to a compound having a structurerepresented by formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the invention relates to a compound having astructure represented by formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; wherein A¹ is selected from optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein A² is selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; or a pharmaceutically acceptablesalt, hydrate, solvate, or polymorph thereof.

In various aspects, n is 0, 1, or 2. Thus, the disclosed compounds cancomprise sulfane (i.e., —S—) moieties, sulfinyl (i.e., —S(O)—) moieties,and/or sulfonyl (i.e., —S(O)₂—) moieties. In a further aspect, n is 1 or2. In a further aspect, n is 2. In a yet further aspect, each of R^(1a)and R^(1c) is F. In a yet further aspect, at least one of R^(1a) andR^(1c) is F. In an even further aspect, each of R^(1b) and R^(1d) ishydrogen.

In a further aspect, the invention relates to a compound having astructure represented by formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In various aspects, n is 0, 1, or 2. Thus, the disclosed compounds cancomprise sulfane (i.e., —S—) moieties, sulfinyl (i.e., —S(O)—) moieties,and/or sulfonyl (i.e., —S(O)₂—) moieties. In a further aspect, n is 1 or2. In a further aspect, n is 2. In a yet further aspect, each of R^(1a)and R^(1c) is F. In a yet further aspect, at least one of R^(1a) andR^(1c) is F. In an even further aspect, each of R^(1b) and R^(1d) ishydrogen.

In a further aspect, a compound can have a structure listed herein. In afurther aspect, the compounds can be selected from two or more of thestructures listed herein. In one aspect, the disclosed compounds do notinclude2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.

In a further aspect, the invention relates to a compound having astructure represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from pyridinyl, pyridinylmethyl, pyridazinyl, pyrimidinyl,5-methylisoxazol-3-yl, benzoxazolyl, benzoisoxazolyl, oxetanyl, andthiazolyl, and A¹ is substituted with 0-2 groups selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkoxyl, and C1-C4 haloalkyl; wherein eachR^(5a)-R^(5e) is independently selected from hydrogen, fluoro, chloro,bromo, iodo, azido, amino, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkoxy, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one ofR^(5a)-R^(5e) is selected from optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; or at least two of R^(5a)-R^(5e)are independently selected from fluoro, chloro, bromo, iodo, azido,amino, alkyl, and alkoxy.

In a further aspect, n is 2. In a further aspect, at least one ofR^(5a)-R^(5e) is selected from optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl. In a further aspect, eachR^(1a)-R^(1d) is hydrogen. In a further aspect, at least one of R^(1a)or R^(1c) is F.

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

In a further aspect, the compound has a structure represented by aformula listed below:

a. R¹ Groups

In one aspect, each R^(1a)-R^(1d) is independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl.

In a further aspect, R^(1a) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(1a) can be hydrogen. As afurther example, R^(1a) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(1a) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(1a)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(1b) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(1b) can be hydrogen. As afurther example, R^(1b) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(1b) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(1b)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(1c) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(1c) can be hydrogen. As afurther example, R^(1c) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(1c) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(1c)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(1d) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(1d) can be hydrogen. As afurther example, R^(1d) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(1d) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(1d)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

It is also contemplated that any two or more of R^(1a)-R^(1d) can beselected to be substituted in a 1,2 (viz. ortho); a 1,3 (viz. meta); a1,4 (viz. para); a 1,2,3; a 1,3,4; a 1,2,4; or a 1,2,3,4 relativeregiochemistry. In a further aspect, each of R^(1b) and R^(1d) ishydrogen. In a further aspect, at least one of R^(1a) or R^(1c) is F. Ina still further aspect, each of R^(1b) and R^(1d) is F.

b. R² Groups

In one aspect, R² is selected from hydrogen, halogen, hydroxyl, thiol,sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. Forexample, R² can be hydrogen. As a further example, R² can be halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl. As a further example, R² can be halogen, hydroxyl, thiol,sulfo, nitro, cyano, alkoxyl, or optionally substituted alkyl. As afurther example, R² can be optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.

c. R³ Groups

In one aspect, wherein R³ comprises two substituents independentlyselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. It isunderstood that the two R³ groups can, if desired, be alternativelyreferred to individually as R^(3a) and R^(3b), as shown below:

For example, R^(3a) can be hydrogen. As a further example, R^(3a) can behalogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl. As a further example, R^(3a) can be halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, or optionally substitutedalkyl. As a further example, R^(3a) can be optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

For example, R^(3b) can be hydrogen. As a further example, R^(3b) can behalogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl. As a further example, R^(3b) can be halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, or optionally substitutedalkyl. As a further example, R^(3b) can be optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

d. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen, a hydrolysable residue, andoptionally substituted alkyl. For example, R⁴ can be hydrogen. As afurther example, R⁴ can be a hydrolysable residue. As a further example,R⁴ can be optionally substituted alkyl.

e. R⁵ Groups

In one aspect, each R^(5a)-R^(5e) is independently selected from H, Cl,Br, F, azido, amino, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkoxy, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl. In a further aspect, R^(5a), R^(5c),and R^(5e) are independently selected from H, Cl, Br, F, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkoxy, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. In a furtheraspect, R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen.

In a further aspect, R^(5a) is selected from H, Cl, Br, F, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkoxy, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. For example,R^(5a) can be hydrogen. As a further example, R^(5a) can be Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, R^(5b) is selected from H, F, Cl, Br, azido, amino,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. Forexample, R^(5b) can be hydrogen. As a further example, R^(5b) can be Cl,Br, F, optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. In afurther aspect, R^(5b) is selected from H, Cl, Br, azido, amino,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;provided that at least one of R^(5b) and R^(5d) is not hydrogen. In astill further aspect, R^(5b) is selected from H, Cl, Br, azido,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;provided that at least one of R^(5b) and R^(5d) is not hydrogen.

In a further aspect, R^(5c) is selected from H, Cl, Br, F, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkoxy, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. For example,R^(5c) can be hydrogen. As a further example, R^(5c) can be Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, R^(5d) is selected from H, F, Cl, Br, azido, amino,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. Forexample, R^(5d) can be hydrogen. As a further example, R^(5d) can be Cl,Br, F, optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. In afurther aspect, R^(5d) is selected from H, Cl, Br, azido, amino,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;provided that at least one of R^(5b) and R^(5d) is not hydrogen. In astill further aspect, R^(5d) is selected from H, Cl, Br, azido,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;provided that at least one of R^(5b) and R^(5d) is not hydrogen.

In a further aspect, R^(5e) is selected from H, Cl, Br, F, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkoxy, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. For example,R^(5e) can be hydrogen. As a further example, R^(5e) can be Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

It is also contemplated that any two or more of R^(5a)-R^(5e) can beselected to be substituted in a 1,2 (viz. ortho); a 1,3 (viz. meta); a1,4 (viz. para); a 1,5; a 1,2,3; a 1,3,4; a 1,2,4; 1,2,5; 1,3,5; 1,4,5;a 1,2,3,4; a 2,3,4,5; or a 1,2,3,4,5 relative regiochemistry. In afurther aspect, each of R^(5b-e) is hydrogen.

In a further aspect, each R^(5a)-R^(5e) is independently selected fromhydrogen, fluoro, chloro, bromo, iodo, azido, amino, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkoxy, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; provided thatat least one of R^(5a)-R^(5e) is selected from optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or at least twoof R^(5a)-R^(5e) are independently selected from fluoro, chloro, bromo,iodo, azido, amino, alkyl, and alkoxy.

f. R⁶ Groups

In one aspect, each R^(6a)-R^(6e) is independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl.

In a further aspect, R^(6a) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(6a) can be hydrogen. As afurther example, R^(6a) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(6a) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(6a)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(6b) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(6b) can be hydrogen. As afurther example, R^(6b) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(6b) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(6b)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(6c) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(6c) can be hydrogen. As afurther example, R^(6c) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(6c) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(6c)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(6d) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(6d) can be hydrogen. As afurther example, R^(6d) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(6d) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(6d)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(6e) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(6e) can be hydrogen. As afurther example, R^(6e) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(6e) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(6e)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

It is also contemplated that any two or more of R^(6a)-R^(6e) can beselected to be substituted in a 1,2 (viz. ortho); a 1,3 (viz. meta); a1,4 (viz. para); a 1,2,3; a 1,3,4; a 1,2,4; or a 1,2,3,4 relativeregiochemistry. In a further aspect, each of R^(6b) and R^(6d) ishydrogen. In a further aspect, at least one of R^(6a) or R^(6c) is F.

g. R⁷ Groups

In one aspect, each R^(7a)-R^(7e) is independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl.

In a further aspect, R^(7a) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(7a) can be hydrogen. As afurther example, R^(7a) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(7a) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(7a)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(7b) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(7b) can be hydrogen. As afurther example, R^(7b) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(7b) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(7b)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(7c) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(7c) can be hydrogen. As afurther example, R^(7c) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(7c) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(7c)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(7d) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(7d) can be hydrogen. As afurther example, R^(7d) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(7d) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(7d)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In a further aspect, R^(7e) is selected from hydrogen, halogen,hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. For example, R^(7e) can be hydrogen. As afurther example, R^(7e) can be halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl. As a furtherexample, R^(7e) can be halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, or optionally substituted alkyl. As a further example, R^(7e)can be optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl.

It is also contemplated that any two or more of R^(7a)-R^(7e) can beselected to be substituted in a 1,2 (viz. ortho); a 1,3 (viz. meta); a1,4 (viz. para); a 1,2,3; a 1,3,4; a 1,2,4; or a 1,2,3,4 relativeregiochemistry. In a further aspect, each of R^(7b) and R^(7d) ishydrogen. In a further aspect, at least one of R^(7a) or R^(7c) is F.

h. R⁸ Groups

In one aspect, R⁸ is selected from hydrogen, optionally substitutedalkyl, optionally substituted alkaryl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. In a furtheraspect, R⁸ is hydrogen. In a further aspect, R⁸ is selected fromoptionally substituted alkyl, optionally substituted alkaryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, R⁸ is selected from hydrogen and a moiety having astructure represented by the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl. In afurther aspect, R⁸ is a moiety having a structure represented by theformula:

i. R⁹ Groups

In one aspect, R⁹ is selected from hydrogen and a moiety having astructure represented by the formula:

wherein R³ comprises two substituents independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein Z is —O—, —S—, or —NA¹-;wherein A¹ is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; and wherein nis 0, 1, or 2.

In a further aspect, R⁹ is a moiety having a structure represented bythe formula:

In a further aspect, R⁹ is a moiety having a structure represented bythe formula:

In an even further aspect, R⁹ is hydrogen, and the compound can bereacted with another compound having a structure represented by theformula:

and then optionally oxidized.

j. A¹ Groups

In one aspect, A¹ is selected from optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. In a further aspect, A¹ is selected from alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl

In a further aspect, A¹ is selected from optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. In a stillfurther aspect, A¹ is selected from optionally substituted alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl. In a yet further aspect, A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, and optionally substitutedheteroaryl. In an even further aspect, C is selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl. Ina still further aspect, A¹ is selected from optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, and optionally substituted aryl.

In a further aspect, A¹ is selected from optionally substitutedoptionally substituted aryl and optionally substituted heteroaryl. In astill further aspect, A¹ is selected from optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl.

In a further aspect, A¹ is optionally substituted alkyl. In a stillfurther aspect, A¹ is optionally substituted cycloalkyl. In a yetfurther aspect, A¹ is selected from optionally substitutedheterocycloalkyl. In an even further aspect, A¹ is optionallysubstituted aryl. In a still further aspect, A¹ is optionallysubstituted heteroaryl.

In a further aspect, A¹ is selected from a structure represented by theformula:

In a further aspect, A¹ is selected from pyridinyl, pyridinylmethyl,pyridazinyl, pyrimidinyl, 5-methylisoxazol-3-yl, benzoxazolyl,benzoisoxazolyl, oxetanyl, and thiazolyl, and A¹ is substituted with 0-2groups selected from halogen, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxyl, andC₁-C₄ haloalkyl. In a further aspect, A¹ is substituted with 0-1 groups.In a further aspect, A¹ is substituted with 1 group. In a furtheraspect, A¹ is unsubstituted.

k. A² Groups

In one aspect, A² is selected from optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. In a further aspect, A² is selected from alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

In a further aspect, A² is selected from optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl. In a stillfurther aspect, A² is selected from optionally substituted alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl. In a yet further aspect, A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, and optionally substitutedheteroaryl. In an even further aspect, A² is selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, and optionally substituted heteroaryl. Ina still further aspect, A² is selected from optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, and optionally substituted aryl.

In a further aspect, A² is selected from optionally substitutedoptionally substituted aryl and optionally substituted heteroaryl. In astill further aspect, A² is selected from optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl.

In a further aspect, A² is optionally substituted alkyl. In a stillfurther aspect, A² is optionally substituted cycloalkyl. In a yetfurther aspect, A² is selected from optionally substitutedheterocycloalkyl. In an even further aspect, A² is optionallysubstituted aryl. In a still further aspect, A² is optionallysubstituted heteroaryl.

In a further aspect, A² is selected from a structure represented by theformula:

l. Alkyl

In various aspects, a particular substituent can be selected to bealkyl, optionally substituted alkyl, or substituted alkyl. In oneaspect, alkyl can be methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, or dodecyl. In one aspect, alkylcan be C₁₋₄, C₁₋₆, C₁₋₈, C₁₋₁₀, or C₁₋₁₂. In a further aspect, alkyl canbe branched or unbranched. In a further aspect, alkyl can beunsubstituted.

If optionally substituted, alkyl can bear, for example, 0, 0-1, 0-2,0-3, 0-4, or 0-5 groups. If substituted, alkyl can bear, for example, 1,2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5, 2-5, 3-5, or 4-5 groups.Suitable groups include, for example, halogen (e.g, fluoro, chloro,bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl, ethyl, propyl, orbutyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl, ethoxyl, propoxyl, orbutoxyl), C1-C4 haloalkyl (e.g., fluoromethyl or chloropropyl), C1-C4polyhaloalkyl (e.g., trifluoromethyl or perfluoroethyl), amino,alkylamino, dialkylamino, nitro, azido, aryl, heteroaryl, cycloalkyl,and heterocycloalkyl.

m. Alkaryl

In various aspects, a particular substituent can be selected to bealkaryl, optionally substituted alkaryl, or substituted alkaryl. In oneaspect, alkaryl can be a moiety having a structure represented by aformula:

wherein m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9, and Ar isaryl. In further aspects, m can be 0-1, 0-2, 0-3, 0-5, 0-7, and 0-9. Ina further aspect, alkaryl can be a moiety having a structure representedby a formula:

wherein m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9, and hetAris heteroaryl. In further aspects, m can be 0-1, 0-2, 0-3, 0-5, 0-7, and0-9.

In one aspect, alkaryl can be C₁₋₄, C₁₋₆, C₁₋₈, C₁₋₁₀, or C₁₋₁₂. In afurther aspect, alkaryl can be branched or unbranched. In a furtheraspect, alkaryl can be monocyclic, bicyclic, or multicyclic. In afurther aspect, alkaryl can be unsubstituted.

If optionally substituted, alkaryl can bear, for example, 0, 0-1, 0-2,0-3, 0-4, or 0-5 groups. If substituted, alkaryl can bear, for example,1, 2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5, 2-5, 3-5, or 4-5groups. Suitable groups include, for example, halogen (e.g, fluoro,chloro, bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl, ethyl,propyl, or butyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl, ethoxyl,propoxyl, or butoxyl), C1-C4 haloalkyl (e.g., fluoromethyl orchloropropyl), C1-C4 polyhaloalkyl (e.g., trifluoromethyl orperfluoroethyl), amino, alkylamino, dialkylamino, nitro, azido, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

n. Cycloalkyl

In various aspects, a particular substituent can be selected to becycloalkyl, optionally substituted cycloalkyl, or substitutedcycloalkyl. In one aspect, cycloalkyl can be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[5.1.0]octyl,bicyclo[6.1.0]nonyl, bicyclo[3.2.0]heptyl, bicyclo[4.2.0]octyl,bicyclo[5.2.0]nonyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl,bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[4.2.1]nonyl,bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, or bicyclo[3.3.1]nonyl. In afurther aspect, cycloalkyl can be cycloalkenyl selected fromcyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl,cyclooctadienyl, cyclononenyl, and cyclononadienyl. In one aspect,cycloalkyl can be C₁₋₄, C₁₋₆, C₁₋₈, C₁₋₁₀, or C₁₋₁₂. In a furtheraspect, cycloalkyl can be monocyclic or bicyclic. In a further aspect,cycloalkyl can be unsubstituted.

If optionally substituted, cycloalkyl can bear, for example, 0, 0-1,0-2, 0-3, 0-4, or 0-5 groups. If substituted, the cycloalkyl can bear,for example, 1, 2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5, 2-5, 3-5,or 4-5 groups. Suitable groups include, for example, halogen (e.g,fluoro, chloro, bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl,ethyl, propyl, or butyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl,ethoxyl, propoxyl, or butoxyl), C1-C4 haloalkyl (e.g., fluoromethyl orchloropropyl), C1-C4 polyhaloalkyl (e.g., trifluoromethyl orperfluoroethyl), amino, alkylamino, dialkylamino, nitro, azido, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

o. Heterocycloalkyl

In various aspects, a particular substituents can be selected to beheterocycloalkyl, optionally substituted heterocycloalkyl, orsubstituted heterocycloalkyl. In one aspect, heterocycloalkyl can becycloalkyl wherein 1, 2, or 3 carbon atoms have been replaced with aheteroatom selected from O, S, and N. It is understood that suchreplacement will alter the number of substitutent groups (e.g., each Oor S substituted for C will decrease the number of substitutent groupsby two, whereas each N substituted for C will decrease the number ofsubstitutent groups by one). In a further aspect, heterocycloalkyl canbe oxirane, oxetane, tetrahydrofuran, tetrahydro-2H-pyran, oxepane,oxocane, dioxirane, dioxetane, dioxolane, dioxane, dioxepane, dioxocane,thiirane, thietane, tetrahydrothiophene, tetrahydro-2H-thiopyran,thiepane, thiocane, dithiirane, dithietane, dithiolane, dithiane,dithiepane, dithiocane, oxathiirane, oxathietane, oxathiolane,oxathiane, oxathiepane, oxathiocane, aziridine, azetidine, pyrrolidone,piperidine, azepane, azocane, diaziridine, diazetidine, imidazolidine,piperazine, diazepane, diazocane, hexahydropyrimidine, triazinane,oxaziridine, oxazetidine, oxazolidine, morpholine, oxazepane, oxazocane,thiaziridine, thiazetidine, thiazolidine, thiomorpholine, thiazepane, orthiazocane. In one aspect, heterocycloalkyl can be C₁₋₄, C₁₋₆, C₁₋₈,C₁₋₁₀, or C₁₋₁₂. In a further aspect, heterocycloalkyl can be monocyclicor bicyclic. In a further aspect, heterocycloalkyl can be unsubstituted.

If optionally substituted, heterocycloalkyl can bear, for example, 0,0-1, 0-2, 0-3, 0-4, or 0-5 groups. If substituted, the heterocycloalkylcan bear, for example, 1, 2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5,2-5, 3-5, or 4-5 groups. Suitable groups include, for example, halogen(e.g, fluoro, chloro, bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl,ethyl, propyl, or butyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl,ethoxyl, propoxyl, or butoxyl), C1-C4 haloalkyl (e.g., fluoromethyl orchloropropyl), C1-C4 polyhaloalkyl (e.g., trifluoromethyl orperfluoroethyl), amino, alkylamino, dialkylamino, nitro, azido, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

p. Aryl

In various aspects, a particular substituent can be selected to be aryl,optionally substituted aryl, or substituted aryl. In one aspect, arylcan be monocyclic or bicyclic. For example, and aryl group can be phenylor naphthyl. In one aspect, the group is phenyl. In a further aspect,aryl can be unsubstituted. If optionally substituted, aryl can bear, forexample, 0, 0-1, 0-2, 0-3, 0-4, or 0-5 groups. If substituted, the arylcan bear, for example, 1, 2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5,2-5, 3-5, or 4-5 groups. Suitable groups include, for example, halogen(e.g, fluoro, chloro, bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl,ethyl, propyl, or butyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl,ethoxyl, propoxyl, or butoxyl), C1-C4 haloalkyl (e.g., fluoromethyl orchloropropyl), C1-C4 polyhaloalkyl (e.g., trifluoromethyl orperfluoroethyl), amino, alkylamino, dialkylamino, nitro, azido, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

q. Heteroaryl

In various aspects, a particular substituents can be selected to beheteroaryl, optionally substituted heteroaryl, or substitutedheteroaryl. In one aspect, heteroaryl can be oxazolyl, isoxazolyl,pyrazolyl, furanyl, pyranyl, imidazolyl, thiophenyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl,benzofuranyl, benzothiophene, indolyl, indazolyl, quinolinyl,naphthyridinyl, benzothiazolyl, benzooxazolyl, benzoimidazolyl, andbenzotriazolyl. In a further aspect, heteroaryl can be 2-pyridinyl,3-pyridinyl, or 4-pyridinyl. In one aspect, heteroaryl can be C₁₋₄,C₁₋₆, or C₁₋₈. In a further aspect, heteroaryl can be monocyclic orbicyclic. In a further aspect, heteroaryl can be unsubstituted.

If optionally substituted, heteroaryl can bear, for example, 0, 0-1,0-2, 0-3, 0-4, or 0-5 groups. If substituted, the heteroaryl can bear,for example, 1, 2, 3, 4, 5, 1-2, 1-3, 2-3, 1-4, 2-4, 3-4, 1-5, 2-5, 3-5,or 4-5 groups. Suitable groups include, for example, halogen (e.g,fluoro, chloro, bromo, or iodo), cyano, C1-C4 alkyl (e.g., methyl,ethyl, propyl, or butyl), hydroxyl, C1-C4 alkyoxy (e.g., methoxyl,ethoxyl, propoxyl, or butoxyl), C1-C4 haloalkyl (e.g., fluoromethyl orchloropropyl), C1-C4 polyhaloalkyl (e.g., trifluoromethyl orperfluoroethyl), amino, alkylamino, dialkylamino, nitro, azido, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl.

2. Example Compounds

Specific examples of compounds of formula (I) include without limitationthe following compounds:

Specific compounds of formula (II) include without limitation thefollowing compounds:

Examples of the compounds of the invention, which can include compoundswithin formula (I) or (II), include2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-(1H-pyrazol-4-yl)benzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-chlorobenzyl)-1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-methoxybenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-bromobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-chloro-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(3-(1H-pyrazol-4-yl)benzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(2-fluoro-3-(1H-pyrazol-3-yl)benzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;2-((1-(2-fluoro-5-(1H-pyrazol-4-yl)benzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;and2-((1-[(3-bromophenyl)methyl]-1H-indol-3-yl)sulfanyl)-N-(5-methyl-1,2-oxazol-3-yl)acetamide.

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present:

In one aspect, a compound can be present as:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as one or more of the followingstructures:

In one aspect, a compound can be present as:

It is understood that the disclosed compounds can be used in connectionwith the disclosed methods, compositions, kits, and uses.

The pharmaceutical acceptable derivatives of the compounds can includeany suitable derivative, such as pharmaceutically acceptable salts asdiscussed below, isomers, radiolabeled analogs, tautomers, and the like.

3. Muscarinic Acetylcholine Receptor M₁ Modulation

The human muscarinic acetylcholine receptor M₁ (mAChR M₁) is a proteinof 479 amino acids encoded by the CHRM1 gene. The molecular weight ofthe unglycosylated protein is about 51,421 kDa and it is a transmembraneGPCR. As described above, the mAChR M₁ is a member of the GPCR Class 1family, or the rhodopsin-like GPCRs, which are characterized bystructural features similar to rhodopsin such as seven transmembranesegments. The muscarinic acetylcholine receptors have the N-terminusoriented to the extracellular face of the membrane and the C-terminuslocated on the cytoplasmic face. The orthosteric binding for naturalligand, acetylcholine, for mAChRs is believed to be located within apocket located within the transmembrane segments. The binding of ligandsto the orthosteric and allosteric sites can be distinguished usingmethods such as those described herein and a variety of other methodsknown to one skilled in the art.

In one aspect, the disclosed compounds potentiate the agonist response(e.g., acetylcholine) of mAChR M₁. In a further aspect, the disclosedcompounds increase mAChR M₁ response to non-maximal concentrations ofagonist in the presence of compound compared to the response to agonistin the absence of compound. The potentiation of mAChR M₁ activity, canbe demonstrated by methodology known in the art. For example, activationof mAChR M₁ activity can be determined by measurement of calcium flux inresponse to agonist, e.g. acetylcholine, in cells loaded with aCa²⁺-sensitive fluorescent dye (e.g., Fluo-4). In a further aspect, thecalcium flux was measured as an increase in fluorescent static ratio. Ina yet further aspect, positive allosteric modulator activity wasanalyzed as a concentration-dependent increase in the EC₂₀ acetylcholineresponse (i.e. the response of mAChR M₁ at a concentration ofacetylcholine that yields 20% of the maximal response).

In one aspect, the disclosed compounds activate mAChR M₁ response as anincrease in calcium fluorescence in mAChR M₁-transfected CHO-K1 cells inthe presence of the compound, compared to the response of equivalentCHO-K1 cells in the absence of the compound. For example, a disclosedcompound can have an EC₅₀ of less than about 10 μM, of less than about 5μM, of less than about 1 μM, of less than about 500 nM, of less thanabout 100 nM, or of less than about 50 nM.

In one aspect, the disclosed compounds exhibit potentiation of mAChR M₁response to acetylcholine as an increase in response to non-maximalconcentrations of acetylcholine in CHO-K1 cells transfected with amammalian mAChR M₁ in the presence of the compound, compared to theresponse to acetylcholine in the absence of the compound. For example,CHO-K1 cells can be transfected with human mAChR M₁. For example, CHO-K1cells can be transfected with rat mAChR M₁. For example, a compound canexhibit positive allosteric modulation of mAChR M₁ with an EC₅₀ of lessthan about 10,000 nM, of less than about 5,000 nM. of less than about1,000 nM, of less than about 500 nM, or of less than about 100 nM.Alternatively, the disclosed compounds exhibit potentiation of mAChR M₁response to acetylcholine as an increase in response to non-maximalconcentrations of acetylcholine in CHO-K1 cells transfected with humanmAChR M₁ in the presence of the compound, compared to the response toacetylcholine in the absence of the compound. For example, a compoundcan exhibit positive allosteric modulation of mAChR M₁ with an EC₅₀ ofless than about 10,000 nM, of less than about 5,000 nM. of less thanabout 1,000 nM, of less than about 500 nM, of less than about 100 nM, orof less than about 50 nM.

Without wishing to be bound by a particular theory, the disclosedcompounds and products of the disclosed methods are believed to bind toan allosteric site distinct from the orthosteric binding site. Further,without wishing to be bound by particular theory, the disclosedcompounds and products of the disclosed methods can bind to anallosteric site that comprises portions of one or more extracellularloops and/or transmembrane segments, and is distinct from theorthosteric binding site. In a further aspect, without wishing to bebound by a particular theory, the disclosed compounds and products ofthe disclosed methods can bind to an allosteric site that comprisesportions of one or more intracellular loops and/or transmembranesegments, and is distinct from the orthosteric binding site. In a stillfurther aspect, without wishing to be bound by particular theory, thedisclosed compounds and products of the disclosed methods can bind to anallosteric site that comprises portions of segments, amino acids, orsub-domains of the mAChR M₁ protein that potentiates interactions of theprotein with other proteins, e.g. G-proteins.

Previous attempts to develop agonists that are highly selective forindividual mAChR subtypes have failed because of the high conservationof the orthosteric ACh binding site. To circumvent problems associatedwith targeting the highly conserved orthosteric ACh binding site, it isbelieved that developing compounds that act at less highly conservedallosteric mAChR sites will afford highly selectiveactivators/modulators.

In various further aspects, the compound activates mAChR M₁ response inmAChR M₁-transfected CHO-K1 cells with an EC₅₀ less than the EC₅₀ forone or more of mAChR M₂, M₃, M₄ or M₅-transfected CHO-K1 cells That is,a disclosed compound can have selectivity for the mAChR M₁ receptorvis-à-vis one or more of the mAChR M₂, M₃, M₄ or M₅ receptors. Forexample, in one aspect, a disclosed compound can activate mAChR M₁response with an EC₅₀ of about 5-fold less than that for mAChR M₂, ofabout 10-fold less than that for mAChR M₂, of about 20-fold less thanthat for mAChR M₂, of about 30-fold less than that for mAChR M₂, or ofabout 50-fold less than that for mAChR M₂. In a further aspect, adisclosed compound can activate mAChR M₁ response with an EC₅₀ of about5-fold less than that for mAChR M₃, of about 10-fold less than that formAChR M₃, of about 20-fold less than that for M₃, of about 30-fold lessthan that for mAChR M₃, or of about 50-fold less than that for mAChR M₃.In a further aspect, a disclosed compound can activate mAChR M₁ responsewith an EC₅₀ of about 5-fold less than that for mAChR M₄, of about10-fold less than that for mAChR M₄, of about 20-fold less than that forM₄, of about 30-fold less than that for mAChR M₄, or of about 50-foldless than that for mAChR M₄. In a further aspect, a disclosed compoundcan activate mAChR M₁ response with an EC₅₀ of about 5-fold less thanthat for mAChR M₅, of about 10-fold less than that for mAChR M₅, ofabout 20-fold less than that for mAChR M₅, of about 30-fold less thanthat for mAChR M₅, or of about 50-fold less than that for mAChR M₅. In afurther aspect, a disclosed compound can activate mAChR M₁ response withan EC₅₀ of about 5-fold less than that for the mAChR M₂, M₃, M₄ or M₅receptors, of about 10-fold less than that for the mAChR M₂, M₃, M₄ orM₅ receptors, of about 20-fold less than that for the mAChR M₂, M₃, M₄or M₅ receptors, of about 30-fold less than that for the mAChR M₂, M₃,M₄ or M₅ receptors, or of about 50-fold less than that for the mAChR M₂,M₃, M₄ or M₅ receptors.

In various further aspects, the compound activates mAChR M₁ response inM₁-transfected CHO-K1 cells with an EC₅₀ of less than about 10 μM andexhibits a selectivity for the M₁ receptor vis-à-vis one or more of themAChR M₂, M₃, M₄ or M₅ receptors. For example, in one aspect, thecompound can have an EC₅₀ of less than about 10 μM, of less than about 5μM, of less than about 1 μM, of less than about 500 nM, of less thanabout 100 nM, or of less than about 50 nM; and the compound can alsoactivate mAChR M₁ response with an EC₅₀ of about 5-fold less than thatfor mAChR M₂, of about 10-fold less than that for mAChR M₂, of about20-fold less than that for mAChR M₂, of about 30-fold less than that formAChR M₂, or of about 50-fold less than that for mAChR M₂. In a furtheraspect, the compound can have an EC₅₀ of less than about 10 μM, of lessthan about 5 μM, of less than about 1 μM, of less than about 500 nM, ofless than about 100 nM, or of less than about 50 nM; and the compoundcan also activate mAChR M₁ response with an EC₅₀ of about 5-fold lessthan that for mAChR M₃, of about 10-fold less than that for mAChR M₃, ofabout 20-fold less than that for mAChR M₃, of about 30-fold less thanthat for mAChR M₃, or of about 50-fold less than that for mAChR M₃. In afurther aspect, the compound can have an EC₅₀ of less than about 10 μM,of less than about 5 μM, of less than about 1 μM, of less than about 500nM, of less than about 100 nM, or of less than about 50 nM; and thecompound can also activate mAChR M₁ response with an EC₅₀ of about5-fold less than that for mAChR M₄, of about 10-fold less than that formAChR M₄, of about 20-fold less than that for mAChR M₄, of about 30-foldless than that for mAChR M₄, or of about 50-fold less than that formAChR M₄. In a further aspect, the compound can have an EC₅₀ of lessthan about 10 μM, of less than about 5 μM, of less than about 1 μM, ofless than about 500 nM, of less than about 100 nM, or of less than about50 nM; and the compound can also activate mAChR M₁ response with an EC₅₀of about 5-fold less than that for mAChR M₅, of about 10-fold less thanthat for mAChR M₅, of about 20-fold less than that for mAChR M₅, ofabout 30-fold less than that for mAChR M₅, or of about 50-fold less thanthat for mAChR M₅. In a further aspect, the compound can have an EC₅₀ ofless than about 10 μM, of less than about 5 μM, of less than about 1 μM,of less than about 500 nM, of less than about 100 nM, or of less thanabout 50 nM; and the compound can also activate mAChR M₁ response withan EC₅₀ of about 5-fold less than that for the mAChR M₂, M₃, M₄ or M₅receptors, of about 10-fold less than that for the mAChR M₂, M₃, M₄ orM₅ receptors, of about 20-fold less than that for the mAChR M₂, M₃, M₄or M₅ receptors, of about 30-fold less than that for the mAChR M₂, M₃,M₄ or M₅ receptors, or of about 50-fold less than that for the mAChR M₂,M₃, M₄ or M₅ receptors.

In one aspect, the compound is a positive allosteric modulator of themuscarinic receptor. Thus, the compounds of the invention can bind tothe muscarinic receptor, and particularly to muscarinic receptor subtypeM₁, which results in an increased efficacy at that receptor for theendogenous agonist. Thus, by positive allosteric modulation, thecompounds indirectly activate the muscarinic receptor subtype M₁. In oneaspect, the compound activates M₁ response in M₁-transfected CHO-K1cells. For example, the compound can have an EC₅₀ for M₁ of less thanabout 10 μM, of less than about 5 μM, of less than about 1 μM, of lessthan about 500 nM, of less than about 100 nM, or of less than about 50nM.

C. Methods of Making the Compounds

In one aspect, the invention relates to methods of making compoundsuseful as positive allosteric activators of the mAChR M₁ receptor, whichcan be useful in the treatment neurological and psychiatric disordersassociated with muscarinic acetylcholine dysfunction and other diseasesin which muscarinic acetylcholine receptors are involved.

The compounds of this invention can be prepared by employing reactionsas shown in the disclosed schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a fewer substituent can be shown where multiplesubstituents are allowed under the definitions disclosed herein. Thus,the following examples are provided so that the invention might be morefully understood, are illustrative only, and should not be construed aslimiting.

In one aspect, the disclosed compounds comprise the products of thesynthetic methods described herein. In a further aspect, the disclosedcompounds comprise a compound produced by a synthetic method describedherein. In a still further aspect, the invention comprises apharmaceutical composition comprising a therapeutically effective amountof the product of the disclosed methods and a pharmaceuticallyacceptable carrier. In a still further aspect, the invention comprises amethod for manufacturing a medicament comprising combining at least onecompound of any of disclosed compounds or at least one product of thedisclosed methods with a pharmaceutically acceptable carrier or diluent.

In a further aspect, the compound produced exhibits positive allostericmodulation of mAChR M₁ response to acetylcholine as an increase inresponse to non-maximal concentrations of acetylcholine in CHO-K1 cellstransfected with rat mAChR M₁ in the presence of the compound, comparedto the response to acetylcholine in the absence of the compound. In afurther aspect, CHO-K1 cells are transfected with human mAChR M₁. In yeta further aspect, human embryonic kidney cells are transfected withmammalian mAChR M₁.

In a further aspect, the compound produced exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmAChR M₁ with an EC₅₀ of less than about 500 nM. In a yet furtheraspect, the compound exhibits positive allosteric modulation of mAChR M₁with an EC₅₀ of less than about 100 nM. In a further aspect, thecompound exhibits positive allosteric modulation of mAChR M₁ with anEC₅₀ of between from about 10,000 nM to about 1 nM. In a yet furtheraspect, the compound exhibits positive allosteric modulation of mAChR M₁with an EC₅₀ of between from about 1,000 nM to about 1 nM. In a stillfurther aspect, the compound exhibits positive allosteric modulation ofmAChR M₁ with an EC₅₀ of between from about 100 nM to about 1 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of between from about 10 nM to about1 nM.

In a further aspect, the compound produced is a positive allostericmodulator of human and rat mAChR M₁ and were selective for mAChR M₁compared to the other four subtypes of muscarinic acetylcholinereceptors (mAChR M₂, M₃, M₄ and M₅).

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed compositions, kits, and uses.

1. Scheme 1

In one aspect, substituted indole analogs of the present invention canbe prepared generically by the synthetic scheme as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, Scheme I can be carried as shown above. The startingmaterial indole can be purchased from commercial suppliers, includeindoles comprising one or more substituents at R^(1a)-R^(1d) such asfluorine. In a first step, an indole derivative is reacted with amercaptoacetate to provide the coupled thioether product. A variety ofconditions can be used for this step, for example, a solution of iodineand potassium iodide. The acetate product can then be hydrolyzed using asuitable reagent, such as lithium hydroxide. The product of thisreaction can then be further reacted with A¹, for example as an amine,e.g., A¹NHR₄, in the presence of an appropriate coupling reagent, suchas PyClu (1-(Chloro-1-pyrrolidinylmethylene)pyrrolidiniumhexafluorophosphate). Optionally, for example when n is 0, the thioethercan be oxidized using an appropriate oxidation reagent, such as oxone.A² can then be attached at the free amine site using a variety ofreaction protocols, such as a nucleophilic coupling reaction, forexample, involving a strong base, such as NaH, and A² attached to aleaving group. Additional steps can be carried out on the product ofScheme 1, for example, to further modify A² and/or A¹.

2. Scheme 2

In one aspect, substituted indole analogs of the present invention canbe prepared generically by the synthetic scheme as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In this synthetic scheme, the amine on the indole ring is coupled to anaryl group comprising a benzylic leaving group, for example a benzylbromide, to provide the target compound.

Additional steps can be carried using the product of Scheme 2. Forexample, as shown in Scheme 3, an A³ can be attached as R^(5d), forexample, using a Pd catalyst and an appropriate aromatic couplingreagent, e.g., A³-B(OH)₂. Such a modification could similarly be made atany one or more of R^(5a)-R^(5d).

3. Scheme 3

In one aspect, substituted indole analogs of the present invention canbe prepared generically by the synthetic scheme as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

4. Scheme 4

In one aspect, substituted indole analogs of the present invention canbe prepared generically by the synthetic scheme as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

5. Scheme 5

In one aspect, substituted indole analogs of the present invention canbe prepared generically by the synthetic scheme as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, the invention relates to a synthetic method comprisingthe steps of: (a) providing a compound having a structure represented bya formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R² is selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; and wherein R⁸ is selected fromhydrogen, optionally substituted alkyl, optionally substituted alkaryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl, and; (b) reacting with a compound having astructure represented by a formula:

wherein R³ comprises two substituents independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein Z is —O—, —S—, or —NA¹-;wherein R⁴ is selected from hydrogen, a hydrolysable residue, andoptionally substituted alkyl; wherein A¹ is selected from optionallysubstituted alkyl, optionally substituted alkaryl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl, and(c) optionally oxidizing, thereby providing a compound having astructure represented by the formula:

wherein n is 0, 1, or 2.

In a further aspect, at least one of R^(1a) and R^(1c) is F. In a stillfurther aspect, the compound provided is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.In a yet further aspect, R⁸ is selected from hydrogen and a moietyhaving a structure represented by the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, R⁸ is selected from hydrogen and a moiety having astructure represented by the formula:

wherein R^(5a), R^(5c), and R^(5e) are independently selected from H,Cl, Br, F, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and wherein R^(5b) and R^(5d) are independentlyselected from H, Cl, Br, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkoxy, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(5b)and R^(5d) is not hydrogen. In a still further aspect, R⁸ is selectedfrom optionally substituted alkyl, optionally substituted alkaryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl. In a yet further aspect, R⁸ is a moiety having astructure represented by the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, R⁸ is hydrogen. In a yet further aspect, R⁸ ishydrogen, the method further comprising: a) optional deprotonation, andb) reaction with A²X, wherein X is a leaving group, thereby providing acompound having a structure represented by the formula:

wherein A² is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl.

In a further aspect, Z is —NA¹-. In a yet further aspect, Z is —O— or—S—. In a still further aspect, Z is —O— or —S—, the method furthercomprising the step of amidation with HNA¹R⁴ to form a compound having astructure represented by the formula:

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —O— or —S—.

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —NA¹-.

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —O— or —S—.

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —NA¹-.

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —O— or —S—.

In a further aspect, the compound provided has a structure representedby the formula:

wherein Z is —NA¹-.

In one aspect, the invention relates to a synthetic method comprisingthe steps of: (a) providing a compound having a structure represented bya formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R² is selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; and wherein R⁹ is selected fromhydrogen and a moiety having a structure represented by the formula:

wherein R³ comprises two substituents independently selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein Z is —O—, —S—, or —NA¹-;wherein A¹ is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; and wherein nis 0, 1, or 2, b) optional deprotonation, and c) reaction with A²X,wherein X is a leaving group, thereby providing a compound having astructure represented by the formula:

wherein A² is selected from optionally substituted alkyl, optionallysubstituted alkaryl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl.

In a further aspect, at least one of R^(1a) and R^(1c) is F. In a stillfurther aspect, the compound provided is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.

In a further aspect, R⁹ is a moiety having a structure represented bythe formula:

In a yet further aspect, R⁹ is a moiety having a structure representedby the formula:

In a still further aspect, R⁹ is hydrogen. In an even further aspect, R⁹is hydrogen, the method further comprising the step of reacting with acompound having a structure represented by the formula:

and optionally oxidizing.

In a further aspect, Z is —NA¹-. In a still further aspect, Z is —O— or—S—. In a yet further aspect, Z is —O— or —S—, the method furthercomprising the step of amidation with HNA¹R⁴ to form a compound having astructure represented by the formula:

In a further aspect, A² is selected from hydrogen and a moiety having astructure represented by the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, A² is selected from hydrogen and a moiety having astructure represented by the formula:

wherein R^(5a), R^(5c), and R^(5e) are independently selected from H,Cl, Br, F, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and wherein R^(5b) and R^(5d) are independentlyselected from H, Cl, Br, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkoxy, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(5b)and R^(5d) is not hydrogen.

In a further aspect, the compound provided has a structure representedby the formula:

In a further aspect, the compound provided has a structure representedby the formula:

In a further aspect, the compound provided has a structure representedby the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In a further aspect, the compound provided has a structure representedby the formula:

wherein each R^(5a)-R^(5e) is independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

It is contemplated that each disclosed methods can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed methods can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

In a further aspect, the compound produced activate mAChR M₁ response asan increase in calcium fluorescence in mAChR M₁-transfected CHO-K1 cellsin the presence of the compound, compared to the response of equivalentCHO-K1 cells in the absence of the compound. For example, a disclosedcompound can have an EC₅₀ of less than about 10 μM, of less than about 5μM, of less than about 1 μM, of less than about 500 nM, of less thanabout 100 nM, or of less than about 50 nM.

In one aspect, the compound produced exhibits potentiation of mAChR M₁response to acetylcholine as an increase in response to non-maximalconcentrations of acetylcholine in CHO-K1 cells transfected with amammalian mAChR M₁ in the presence of the compound, compared to theresponse to acetylcholine in the absence of the compound. For example,CHO-K1 cells can be transfected with human mAChR M₁. For example, CHO-K1cells can be transfected with rat mAChR M₁. For example, a compound canexhibit positive allosteric modulation of mAChR M₁ with an EC₅₀ of lessthan about 10,000 nM, of less than about 5,000 nM. of less than about1,000 nM, of less than about 500 nM, or of less than about 100 nM.Alternatively, the disclosed compounds exhibit potentiation of mAChR M₁response to acetylcholine as an increase in response to non-maximalconcentrations of acetylcholine in CHO-K1 cells transfected with humanmAChR M₁ in the presence of the compound, compared to the response toacetylcholine in the absence of the compound. For example, a compoundcan exhibit positive allosteric modulation of mAChR M₁ with an EC₅₀ ofless than about 10,000 nM, of less than about 5,000 nM. of less thanabout 1,000 nM, of less than about 500 nM, of less than about 100 nM, orof less than about 50 nM.

In various further aspects, the compound activates mAChR M₁ response inmAChR M₁-transfected CHO-K1 cells with an EC₅₀ less than the EC₅₀ forone or more of mAChR M₂, M₃, M₄ or M₅-transfected CHO-K1 cells That is,a disclosed compound can have selectivity for the mAChR M₁ receptorvis-à-vis one or more of the mAChR M₂, M₃, M₄ or M₅ receptors. Forexample, in one aspect, a disclosed compound can activate mAChR M₁response with an EC₅₀ of about 5-fold less than that for mAChR M₂, ofabout 10-fold less than that for mAChR M₂, of about 20-fold less thanthat for mAChR M₂, of about 30-fold less than that for mAChR M₂, or ofabout 50-fold less than that for mAChR M₂. In a further aspect, adisclosed compound can activate mAChR M₁ response with an EC₅₀ of about5-fold less than that for mAChR M₃, of about 10-fold less than that formAChR M₃, of about 20-fold less than that for M₃, of about 30-fold lessthan that for mAChR M₃, or of about 50-fold less than that for mAChR M₃.In a further aspect, a disclosed compound can activate mAChR M₁ responsewith an EC₅₀ of about 5-fold less than that for mAChR M₄, of about10-fold less than that for mAChR M₄, of about 20-fold less than that forM₄, of about 30-fold less than that for mAChR M₄, or of about 50-foldless than that for mAChR M₄. In a further aspect, a disclosed compoundcan activate mAChR M₁ response with an EC₅₀ of about 5-fold less thanthat for mAChR M₅, of about 10-fold less than that for mAChR M₅, ofabout 20-fold less than that for mAChR M₅, of about 30-fold less thanthat for mAChR M₅, or of about 50-fold less than that for mAChR M₅. In afurther aspect, a disclosed compound can activate mAChR M₁ response withan EC₅₀ of about 5-fold less than that for the mAChR M₂, M₃, M₄ or M₅receptors, of about 10-fold less than that for the mAChR M₂, M₃, M₄ orM₅ receptors, of about 20-fold less than that for the mAChR M₂, M₃, M₄or M₅ receptors, of about 30-fold less than that for the mAChR M₂, M₃,M₄ or M₅ receptors, or of about 50-fold less than that for the mAChR M₂,M₃, M₄ or M₅ receptors.

In various further aspects, the compound activates mAChR M₁ response inM₁-transfected CHO-K1 cells with an EC₅₀ of less than about 10 μM andexhibits a selectivity for the M₁ receptor vis-à-vis one or more of themAChR M₂, M₃, M₄ or M₅ receptors. For example, in one aspect, thecompound can have an EC₅₀ of less than about 10 μM, of less than about 5μM, of less than about 1 μM, of less than about 500 nM, of less thanabout 100 nM, or of less than about 50 nM; and the compound can alsoactivate mAChR M₁ response with an EC₅₀ of about 5-fold less than thatfor mAChR M₂, of about 10-fold less than that for mAChR M₂, of about20-fold less than that for mAChR M₂, of about 30-fold less than that formAChR M₂, or of about 50-fold less than that for mAChR M₂. In a furtheraspect, the compound can have an EC₅₀ of less than about 10 μM, of lessthan about 5 μM, of less than about 1 μM, of less than about 500 nM, ofless than about 100 nM, or of less than about 50 nM; and the compoundcan also activate mAChR M₁ response with an EC₅₀ of about 5-fold lessthan that for mAChR M₃, of about 10-fold less than that for mAChR M₃, ofabout 20-fold less than that for mAChR M₃, of about 30-fold less thanthat for mAChR M₃, or of about 50-fold less than that for mAChR M₃. In afurther aspect, the compound can have an EC₅₀ of less than about 10 μM,of less than about 5 μM, of less than about 1 μM, of less than about 500nM, of less than about 100 nM, or of less than about 50 nM; and thecompound can also activate mAChR M₁ response with an EC₅₀ of about5-fold less than that for mAChR M₄, of about 10-fold less than that formAChR M₄, of about 20-fold less than that for mAChR M₄, of about 30-foldless than that for mAChR M₄, or of about 50-fold less than that formAChR M₄. In a further aspect, the compound can have an EC₅₀ of lessthan about 10 μM, of less than about 5 μM, of less than about 1 μM, ofless than about 500 nM, of less than about 100 nM, or of less than about50 nM; and the compound can also activate mAChR M₁ response with an EC₅₀of about 5-fold less than that for mAChR M₅, of about 10-fold less thanthat for mAChR M₅, of about 20-fold less than that for mAChR M₅, ofabout 30-fold less than that for mAChR M₅, or of about 50-fold less thanthat for mAChR M₅. In a further aspect, the compound can have an EC₅₀ ofless than about 10 μM, of less than about 5 μM, of less than about 1 μM,of less than about 500 nM, of less than about 100 nM, or of less thanabout 50 nM; and the compound can also activate mAChR M₁ response withan EC₅₀ of about 5-fold less than that for the mAChR M₂, M₃, M₄ or M₅receptors, of about 10-fold less than that for the mAChR M₂, M₃, M₄ orM₅ receptors, of about 20-fold less than that for the mAChR M₂, M₃, M₄or M₅ receptors, of about 30-fold less than that for the mAChR M₂, M₃,M₄ or M₅ receptors ceptors, or of about 50-fold less than that for themAChR M₂, M₃, M₄ or M₅ receptors.

In one aspect, the compound is a positive allosteric modulator of themuscarinic receptor. Thus, the compounds of the invention can bind tothe muscarinic receptor, and particularly to muscarinic receptor subtypeM₁, which results in an increased efficacy at that receptor for theendogenous agonist. Thus, by positive allosteric modulation, thecompounds indirectly activate the muscarinic receptor subtype M₁. In oneaspect, the compound activates M₁ response in M₁-transfected CHO-K1cells. For example, the compound can have an EC₅₀ for M₁ of less thanabout 10 μM, of less than about 5 μM, of less than about 1 μM, of lessthan about 500 nM, of less than about 100 nM, or of less than about 50nM.

D. Pharmaceutical Compositions

In one aspect, the invention relates to pharmaceutical compositionscomprising the disclosed compounds. That is, a pharmaceuticalcomposition can be provided comprising a therapeutically effectiveamount of at least one disclosed compound, at least one product of adisclosed method, or a pharmaceutically acceptable salt, solvate,hydrate, or polymorph thereof, and a pharmaceutically acceptablecarrier. In a further aspect, the effective amount is a therapeuticallyeffective amount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition exhibits positiveallosteric modulation of mAChR M₁ with an EC₅₀ of less than about 10,000nM. In a still further aspect, the pharmaceutical composition exhibitspositive allosteric modulation of mAChR M₁ with an EC₅₀ of less thanabout 5,000 nM. In an even further aspect the pharmaceutical compositionexhibits positive allosteric modulation of mAChR M₁ with an EC₅₀ of lessthan about 1,000 nM. In a further aspect, the pharmaceutical compositionexhibits positive allosteric modulation of mAChR M₁ with an EC₅₀ of lessthan about 500 nM. In a yet further aspect, the pharmaceuticalcomposition exhibits positive allosteric modulation of mAChR M₁ with anEC₅₀ of less than about 100 nM. In a further aspect, the pharmaceuticalcomposition exhibits positive allosteric modulation of mAChR M₁ with anEC₅₀ of between from about 10,000 nM to about 1 nM. In a yet furtheraspect, the pharmaceutical composition exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of between from about 1,000 nM toabout 1 nM. In a still further aspect, the pharmaceutical compositionexhibits positive allosteric modulation of mAChR M₁ with an EC₅₀ ofbetween from about 100 nM to about 1 nM. In an even further aspect, thepharmaceutical composition exhibits positive allosteric modulation ofmAChR M₁ with an EC₅₀ of between from about 10 nM to about 1 nM.

In one aspect, the pharmaceutical composition is used to treat a mammal.In a yet further aspect, the mammal is a human. In a further aspect, themammal has been diagnosed with a need for treatment of the disorderprior to the administering step. In a further aspect, the mammal hasbeen identified to be in need of treatment of the disorder. In a furtheraspect, the pharmaceutical composition is used to treat a neurologicaland/or psychiatric disorder. In a yet further aspect, the disorder isassociated with mAChR M₁ dysfunction.

In a further aspect, the pharmaceutical composition is used to treat aneurological and/or psychiatric disorder. In a still further aspect, thedisorder is Alzheimer's disease. In a yet further aspect, disorder isselected from psychosis, schizophrenia, conduct disorder, disruptivebehavior disorder, bipolar disorder, psychotic episodes of anxiety,anxiety associated with psychosis, psychotic mood disorders such assevere major depressive disorder; mood disorders associated withpsychotic disorders, acute mania, depression associated with bipolardisorder, mood disorders associated with schizophrenia, behavioralmanifestations of mental retardation, conduct disorder, autisticdisorder; movement disorders, Tourette's syndrome, akinetic-rigidsyndrome, movement disorders associated with Parkinson's disease,tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

In certain aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases oracids. When the compound of the present invention is acidic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic bases, including inorganic bases and organic bases.Salts derived from such inorganic bases include aluminum, ammonium,calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium,manganese (-ic and -ous), potassium, sodium, zinc and the like salts.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, as well as cyclic amines and substituted amines such asnaturally occurring and synthesized substituted amines. Otherpharmaceutically acceptable organic non-toxic bases from which salts canbe formed include ion exchange resins such as, for example, arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

As used herein, the term “pharmaceutically acceptable non-toxic acids”,includes inorganic acids, organic acids, and salts prepared therefrom,for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

In practice, the compounds of the invention, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier can take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, and/or pharmaceutically acceptable salt(s) thereof, can alsobe administered by controlled release means and/or delivery devices. Thecompositions can be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention can include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of the compounds of the invention. The compounds of theinvention, or pharmaceutically acceptable salts thereof, can also beincluded in pharmaceutical compositions in combination with one or moreother therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In the treatment conditions which require negative allosteric modulationof muscarinic acetylcholine receptoractivity an appropriate dosage levelwill generally be about 0.01 to 500 mg per kg patient body weight perday and can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably 0.5 to 100 mg/kg per day. A suitable dosage level can beabout 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, orabout 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the from of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage of the patient to be treated. Thecompound can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosing regimen can be adjusted toprovide the optimal therapeutic response.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors. Such factorsinclude the age, body weight, general health, sex, and diet of thepatient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of theparticular disease undergoing therapy.

The present invention is further directed to a method for themanufacture of a medicament for modulating muscarinic acetylcholinereceptor activity (e.g., treatment of one or more neurological and/orpsychiatric disorder associated with acetylcholine dysfunction) inmammals (e.g., humans) comprising combining one or more disclosedcompounds, products, or compositions with a pharmaceutically acceptablecarrier or diluent. Thus, in one aspect, the invention relates to amethod for manufacturing a medicament comprising combining at least onedisclosed compound or at least one disclosed product with apharmaceutically acceptable carrier or diluent.

The disclosed pharmaceutical compositions can further comprise othertherapeutically active compounds, which are usually applied in thetreatment of the above mentioned pathological conditions.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

E. Methods of Using the Compounds and Compositions

Also provided is a method of use of a disclosed compound, composition,or medicament. In one aspect, the method of use is directed to thetreatment of a disorder. In a further aspect, the disclosed compoundscan be used as single agents or in combination with one or more otherdrugs in the treatment, prevention, control, amelioration or reductionof risk of the aforementioned diseases, disorders and conditions forwhich the compound or the other drugs have utility, where thecombination of drugs together are safer or more effective than eitherdrug alone. The other drug(s) can be administered by a route and in anamount commonly used therefore, contemporaneously or sequentially with adisclosed compound. When a disclosed compound is used contemporaneouslywith one or more other drugs, a pharmaceutical composition in unitdosage form containing such drugs and the disclosed compound ispreferred. However, the combination therapy can also be administered onoverlapping schedules. It is also envisioned that the combination of oneor more active ingredients and a disclosed compound can be moreefficacious than either as a single agent.

In one aspect, the compounds can be coadministered with anti-Alzheimer'sagents, beta-secretase inhibitors, gamma-secretase inhibitors,orthosteric muscarinic agonists, muscarinic potentiators, cholinesteraseinhibitors, HMG-CoA reductase inhibitors, NSAIDs and anti-amyloidantibodies. In a further aspect, the compounds can be administered incombination with sedatives, hypnotics, anxiolytics, antipsychotics(typical and atypical), selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyT1inhibitors and the like such as, but not limited to: risperidone,clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium,phenobarbitol, and salts thereof and combinations thereof.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Treatment Methods

The compounds disclosed herein are useful for treating, preventing,ameliorating, controlling or reducing the risk of a variety of disorderswherein the patient or subject would benefit from selective positiveallosteric modulation of the M₁ receptor. In one aspect, a treatment caninclude selective M₁ receptor modulation to an extent effective toaffect cholinergic activity. Thus, a disorder can be associated withcholinergic activity, for example cholinergic hypofunction. In oneaspect, provided is a method of treating or preventing a disorder in asubject comprising the step of administering to the subject at least onedisclosed compound; at least one disclosed pharmaceutical composition;and/or at least one disclosed product in a dosage and amount effectiveto treat the disorder in the subject.

Also provided is a method for the treatment of one or more disorders,for which muscarinic receptor activation is predicted to be beneficial,in a subject comprising the step of administering to the subject atleast one disclosed compound; at least one disclosed pharmaceuticalcomposition; and/or at least one disclosed product in a dosage andamount effective to treat the disorder in the subject.

The invention is directed at the use of described chemical compositionsto treat diseases or disorders in patients (preferably human) whereinmuscarinic receptor activation would be predicted to have a therapeuticeffect, such as Alzheimer's disease (both palliative cognitive anddisease-modifying), cognitive impairment, schizophrenia, pain disorders(including acute pain, neuropathic pain and inflammatory pain), andsleep disorders, by administering one or more disclosed compounds orproducts.

In one aspect, provided is a method for treating or preventing anxiety,comprising: administering to a subject at least one disclosed compound;at least one disclosed pharmaceutical composition; and/or at least onedisclosed product in a dosage and amount effective to treat the disorderin the subject. At present, the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV) (1994, AmericanPsychiatric Association, Washington, D.C.), provides a diagnostic toolfor disorders including anxiety and related disorders. These include:panic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobia, social phobia, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, substance-induced anxiety disorder and anxiety disorder nototherwise specified.

Also provided is a method for the treatment of a disorder in a mammalcomprising the step of administering to the mammal at least onedisclosed compound, composition, or medicament.

In one aspect, the NMDA receptor is central to a wide range of CNSprocesses, and plays a role in a variety of disease states in humans orother species. The action of the M₁ receptor potentiates NMDA receptorfunction, which increases activation of the NMDA receptor followingglutamate release from the presynaptic terminal. Changes inNMDA-mediated neurotransmission have been implicated in certainneuropsychiatric disorders such as dementia, depression and psychoses,for example schizophrenia, and learning and memory disorders, forexample attention deficit disorders and autism.

In one aspect, the disclosed compounds have utility in treating avariety of neurological and psychiatric disorders, including one or moreof the following conditions or diseases: schizophrenia or psychosisincluding schizophrenia (paranoid, disorganized, catatonic orundifferentiated), schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced or drug-induced (phencyclidine, ketamine and otherdissociative anaesthetics, amphetamine and other psychostimulants andcocaine) psychosispsychotic disorder, psychosis associated withaffective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, or illness associated with psychosis(such as major depression, manic depressive (bipolar) disorder,Alzheimer's disease and post-traumatic stress syndrome), including boththe positive and the negative symptoms of schizophrenia and otherpsychoses; cognitive disorders including dementia (associated withAlzheimer's disease, ischemia, multi-infarct dementia, trauma, vascularproblems or stroke, HW disease, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia,other general medical conditions or substance abuse); delirium, amnesticdisorders or age-related cognitive decline; anxiety disorders includingacute stress disorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance, dependence or withdrawal from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);obesity, bulimia nervosa and compulsive eating disorders; bipolardisorders, mood disorders including depressive disorders; depressionincluding unipolar depression, seasonal depression and post-partumdepression, premenstrual syndrome (PMS) and premenstrual dysphoricdisorder (PDD), mood disorders due to a general medical condition, andsubstance-induced mood disorders; learning disorders, pervasivedevelopmental disorder including autistic disorder, attention disordersincluding attention-deficit hyperactivity disorder (ADHD) and conductdisorder; NMDA receptor-related disorders such as autism, depression,benign forgetfulness, childhood learning disorders and closed headinjury; movement disorders, including akinesias and akinetic-rigidsyndromes (including Parkinson's disease, drug-induced parkinsonism,postencephalitic parkinsonism, progressive supranuclear palsy, multiplesystem atrophy, corticobasal degeneration, parkinsonism-ALS dementiacomplex and basal ganglia calcification), medication-inducedparkinsonism (such as neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxysmal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

In a specific aspect, the present invention provides a method fortreating cognitive disorders, comprising: administering to a patient inneed thereof an effective amount of a compound of the present invention.Particular cognitive disorders are dementia, delirium, amnesticdisorders and age-related cognitive decline. At present, the textrevision of the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-W-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes cognitivedisorders including dementia, delirium, amnestic disorders andage-related cognitive decline. As used herein, the term “cognitivedisorders” includes treatment of those mental disorders as described inDSM-W-TR. The skilled artisan will recognize that there are alternativenomenclatures, nosologies and classification systems for mentaldisorders, and that these systems evolve with medical and scientificprogress. Thus the term “cognitive disorders” is intended to includelike disorders that are described in other diagnostic sources. Inanother specific embodiment, the present invention provides a method fortreating anxiety disorders, comprising: administering to a patient inneed thereof an effective amount of a compound of the present invention.Particular anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack. At present, the textrevision of the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes anxietydisorders are generalized anxiety disorder, obsessive-compulsivedisorder and panic attack. As used herein, the term “anxiety disorders”includes treatment of those mental disorders as described in DSM-W-TR.The skilled artisan will recognize that there are alternativenomenclatures, nosologies and classification systems for mentaldisorders, and that these systems evolve with medical and scientificprogress. Thus the term “anxiety disorders” is intended to include likedisorders that are described in other diagnostic sources.

In a further specific aspect, the present invention provides a methodfor treating schizophrenia or psychosis comprising: administering to apatient in need thereof an effective amount of a compound of the presentinvention. Particular schizophrenia or psychosis pathologies areparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-W-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

In a further specific aspect, the present invention provides a methodfor treating substance-related disorders and addictive behaviors,comprising: administering to a patient in need thereof an effectiveamount of a compound of the present invention. Particularsubstance-related disorders and addictive behaviors are persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder induced by substance abuse; and tolerance of, dependence on orwithdrawal from substances of abuse. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder induced by substance abuse; and tolerance of, dependence on orwithdrawal from substances of abuse. As used herein, the term“substance-related disorders and addictive behaviors” includes treatmentof those mental disorders as described in DSM-IV-TR. The skilled artisanwill recognize that there are alternative nomenclatures, nosologies andclassification systems for mental disorders, and that these systemsevolve with medical and scientific progress. Thus the term“substance-related disorders and addictive behaviors” is intended toinclude like disorders that are described in other diagnostic sources.

In a still further aspect, the present invention provides a method fortreating pain, comprising: administering to a patient in need thereof aneffective amount of a compound of the present invention. Particular painembodiments are bone and joint pain (osteoarthritis), repetitive motionpain, dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain and neuropathic pain.

In a further aspect, the present invention provides a method fortreating obesity or eating disorders associated with excessive foodintake and complications associated therewith, comprising: administeringto a patient in need thereof an effective amount of a compound of thepresent invention. At present, obesity is included in the tenth editionof the International Classification of Diseases and Related HealthProblems (ICD-10) (1992 World Health Organization) as a general medicalcondition. The text revision of the fourth edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV-TR) (2000, AmericanPsychiatric Association, Washington D.C.) provides a diagnostic toolthat includes obesity in the presence of psychological factors affectingmedical condition. As used herein, the term “obesity or eating disordersassociated with excessive food intake” includes treatment of thosemedical conditions and disorders described in ICD-10 and DSM-W-TR. Theskilled artisan will recognize that there are alternative nomenclatures,nosologies and classification systems for general medical conditions,and that these systems evolve with medical and scientific progress.Thus, the term “obesity or eating disorders associated with excessivefood intake” is intended to include like conditions and disorders thatare described in other diagnostic sources.

The compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein. The compounds are further usefulin a method for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents.

The present invention is further directed to administration of aselective M₁ receptor modulator for improving treatment outcomes in thecontext of cognitive or behavioral therapy. That is, in one aspect, theinvention relates to a cotherapeutic method comprising the step ofadministering to a mammal an effective amount and dosage of at least onecompound of the invention in connection with cognitive or behavioraltherapy.

In a further aspect, administration improves treatment outcomes in thecontext of cognitive or behavioral therapy. Administration in connectionwith cognitive or behavioral therapy can be continuous or intermittent.Administration need not be simultaneous with therapy and can be before,during, and/or after therapy. For example, cognitive or behavioraltherapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or afteradministration of the compound. As a further example, cognitive orbehavioral therapy can be provided within 1, 2, 3, or 4 weeks before orafter administration of the compound. As a still further example,cognitive or behavioral therapy can be provided before or afteradministration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 half-lives of the administered compound.

In one aspect, the disclosed compounds can be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichdisclosed compounds or the other drugs can have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) can be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and a disclosed compound is preferred. However, thecombination therapy can also include therapies in which a disclosedcompound and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the disclosedcompounds and the other active ingredients can be used in lower dosesthan when each is used singly.

Accordingly, the pharmaceutical compositions include those that containone or more other active ingredients, in addition to a compound of thepresent invention.

The above combinations include combinations of a disclosed compound notonly with one other active compound, but also with two or more otheractive compounds. Likewise, disclosed compounds can be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which disclosed compounds are useful. Such other drugscan be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to a disclosedcompound is preferred. Accordingly, the pharmaceutical compositionsinclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of a disclosed compound to the second active ingredientcan be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined withanother agent, the weight ratio of a disclosed compound to the otheragent will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations a disclosed compound and other active agents can beadministered separately or in conjunction. In addition, theadministration of one element can be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Accordingly, the subject compounds can be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the disclosed compounds. The subject compound andthe other agent can be coadministered, either in concomitant therapy orin a fixed combination.

In one aspect, the compound can be employed in combination withanti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies. In another embodiment, thesubject compound can be employed in combination with sedatives,hypnotics, anxiolytics, antipsychotics, antianxiety agents,cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, alprazolam, amisulpride,amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide,clorethate, chlorpromazine, clozapine, cyprazepam, desipramine,dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine,doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproclone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound can be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In a further aspect, the compound can be employed in combination withlevodopa (with or without a selective extracerebral decarboxylaseinhibitor such as carbidopa or benserazide), anticholinergics such asbiperiden (optionally as its hydrochloride or lactate salt) andtrihexyphenidyl(benzhexyl)hydrochloride, COMT inhibitors such asentacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptorantagonists, cholinergic agonists, NMDA receptor antagonists, serotoninreceptor antagonists and dopamine receptor agonists such as alentemol,bromocriptine, fenoldopam, lisuride, naxagolide, pergolide andpramipexole. It will be appreciated that the dopamine agonist can be inthe form of a pharmaceutically acceptable salt, for example, alentemolhydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolidehydrochloride and pergolide mesylate. Lisuride and pramipexol arecommonly used in a non-salt form.

In a further aspect, the compound can be employed in combination with acompound from the phenothiazine, thioxanthene, heterocyclicdibenzazepine, butyrophenone, diphenylbutylpiperidine and indoloneclasses of neuroleptic agent. Suitable examples of phenothiazinesinclude chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine and trifluoperazine. Suitable examples ofthioxanthenes include chlorprothixene and thiothixene. An example of adibenzazepine is clozapine. An example of a butyrophenone ishaloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundcan be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound can beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexyl, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In one aspect, the compound can be employed in combination with ananti-depressant or anti-anxiety agent, including norepinephrine reuptakeinhibitors (including tertiary amine tricyclics and secondary aminetricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamineoxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase(RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs),corticotropin releasing factor (CRF) antagonists, α-adrenoreceptorantagonists, neurokinin-1 receptor antagonists, atypicalanti-depressants, benzodiazepines, 5-HT1A agonists or antagonists,especially 5-HT1A partial agonists, and corticotropin releasing factor(CRF) antagonists. Specific agents include: amitriptyline, clomipramine,doxepin, imipramine and trimipramine; amoxapine, desipramine,maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine,paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromineand selegiline; moclobemide: venlafaxine; duloxetine; aprepitant;bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam,chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam,lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone andipsapirone, and pharmaceutically acceptable salts thereof.

In the treatment of conditions which require activation of themuscarinic receptor an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level can be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20,25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and1000 milligrams of the active ingredient for the symptomatic adjustmentof the dosage to the patient to be treated. The compounds can beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day. This dosage regimen can be adjusted to provide theoptimal therapeutic response. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientcan be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Thus, in one aspect, the invention relates to methods for activating ormodulating muscarinic receptor in at least one cell, comprising the stepof contacting the at least one cell with at least one compound of theinvention, in an amount effective to modulate or activate mAChR M₁activity response in the at least one cell. In a further aspect, thecell is mammalian, for example human. In a further aspect, the cell hasbeen isolated from a subject prior to the contacting step. In a furtheraspect, contacting is via administration to a subject.

A. Treating a Disorder Associated with Muscarinic Acetylcholine ReceptorActivity

In one aspect, the invention relates to a method for the treatment of aneurological and/or psychiatric disorder associated with muscarinicacetylcholine receptor dysfunction in a mammal comprising the step ofadministering to the mammal an effective amount of least one compoundhaving a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered has a structurerepresented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound. In a stillfurther aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 10,000 nM. In astill further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 5,000 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits positive allosteric modulation ofmAChR M₁ with an EC₅₀ of less than about 500 nM. In a yet furtheraspect, the compound exhibits positive allosteric modulation of mAChR M₁with an EC₅₀ of less than about 100 nM. In a further aspect, thecompound exhibits positive allosteric modulation of mAChR M₁ with anEC₅₀ of between from about 10,000 nM to about 1 nM. In a yet furtheraspect, the compound exhibits positive allosteric modulation of mAChR M₁with an EC₅₀ of between from about 1,000 nM to about 1 nM. In a stillfurther aspect, the compound exhibits positive allosteric modulation ofmAChR M₁ with an EC₅₀ of between from about 100 nM to about 1 nM. In aneven further aspect, the compound exhibits positive allostericmodulation of mAChR M₁ with an EC₅₀ of between from about 10 nM to about1 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In a further aspect, the method furthercomprises the step of identifying a mammal in need of treatment of thedisorder. In a further aspect, the disorder is a neurological and/orpsychiatric disorder associated with mAChR M₁ dysfunction.

In a further aspect, the disorder is Alzheimer's disease. In a yetfurther aspect, disorder is selected from psychosis, schizophrenia,conduct disorder, disruptive behavior disorder, bipolar disorder,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders, acute mania, depressionassociated with bipolar disorder, mood disorders associated withschizophrenia, behavioral manifestations of mental retardation, conductdisorder, autistic disorder; movement disorders, Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

b. Potentiation of Muscarinic Acetylcholine Receptor Activity

In one aspect, the invention relates to a method for potentiation ofmuscarinic acetylcholine receptor activity in a mammal comprising thestep of administering to the mammal an effective amount of least onecompound having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered has a structuredrepresented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound. In a stillfurther aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, the compound exhibits potentiation of mAChR M₁ withan EC₅₀ of less than about 10,000 nM. In a still further aspect, thecompound exhibits potentiation of mAChR M₁ with an EC₅₀ of less thanabout 5,000 nM. In an even further aspect, the compound exhibitspotentiation of mAChR M₁ with an EC₅₀ of less than about 1,000 nM. In afurther aspect, the compound exhibits potentiation of mAChR M₁ with anEC₅₀ of less than about 500 nM. In a yet further aspect, the compoundpotentiation of mAChR M₁ with an EC₅₀ of less than about 100 nM. In afurther aspect, the compound exhibits potentiation of mAChR M₁ with anEC₅₀ of between from about 10,000 nM to about 1 nM. In a yet furtheraspect, the compound exhibits potentiation of mAChR M₁ with an EC₅₀ ofbetween from about 1,000 nM to about 1 nM. In a still further aspect,the compound exhibits potentiation of mAChR M₁ with an EC₅₀ of betweenfrom about 100 nM to about 1 nM. In an even further aspect, the compoundexhibits potentiation of mAChR M₁ with an EC₅₀ of between from about 10nM to about 1 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for potentiation of muscarinicacetylcholine receptor activity prior to the administering step. In afurther aspect, the method further comprises the step of identifying amammal in need of potentiating muscarinic acetylcholine receptoractivity. In a further aspect, the potentiation of muscarinicacetylcholine receptor activity is associated with mAChR M₁ dysfunction.

In a further aspect, the potentiation of muscarinic acetylcholinereceptor activity is potentiation of mAChR M₁ activity. In a yet furtheraspect, the potentiation of mAChR M₁ activity treats a disorderassociated with mAChR M₁ activity in the mammal. In a still furtheraspect, the mammal has been diagnosed with a need for treatment of thedisorder prior to the administering step. In an even further aspect,treatment further comprises the step of identifying a mammal in need oftreatment of the disorder.

In a further aspect, potentiation of muscarinic acetylcholine receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mAChR M₁ dysfunction. In astill further aspect, the disorder is Alzheimer's disease. In a yetfurther aspect, disorder is selected from psychosis, schizophrenia,conduct disorder, disruptive behavior disorder, bipolar disorder,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders, acute mania, depressionassociated with bipolar disorder, mood disorders associated withschizophrenia, behavioral manifestations of mental retardation, conductdisorder, autistic disorder; movement disorders, Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

c. Partial Agonism of Muscarinic Acetylcholine Receptor Activity

In one aspect, the invention relates to a method for partial agonism ofmuscarinic acetylcholine receptor activity in a mammal comprising thestep of administering to the mammal a therapeutically effective amountof least one compound having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered has a structurerepresented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound. In a stillfurther aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, the compound exhibits partial agonism of mAChR M₁with an EC₅₀ of less than about 10,000 nM. In a still further aspect,the compound exhibits partial agonism of mAChR M₁ with an EC₅₀ of lessthan about 5,000 nM. In an even further aspect, the compound exhibitspartial agonism of mAChR M₁ with an EC₅₀ of less than about 1,000 nM. Ina further aspect, the compound exhibits partial agonism of mAChR M₁ withan EC₅₀ of less than about 500 nM. In a yet further aspect, the compoundpartial agonism of mAChR M₁ with an EC₅₀ of less than about 100 nM. In afurther aspect, the compound exhibits partial agonism of mAChR M₁ withan EC₅₀ of between from about 10,000 nM to about 1 nM. In a yet furtheraspect, the compound exhibits partial agonism of mAChR M₁ with an EC₅₀of between from about 1,000 nM to about 1 nM. In a still further aspect,the compound exhibits partial agonism of mAChR M₁ with an EC₅₀ ofbetween from about 100 nM to about 1 nM. In an even further aspect, thecompound exhibits partial agonism of mAChR M₁ with an EC₅₀ of betweenfrom about 10 nM to about 1 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for partial agonism of muscarinicacetylcholine receptor activity prior to the administering step. In afurther aspect, the method further comprises the step of identifying amammal in need of partial agonism of muscarinic acetylcholine receptoractivity. In a further aspect, the partial agonism of muscarinicacetylcholine receptor activity is associated with mAChR M₁ dysfunction.

In a further aspect, the partial agonism of muscarinic acetylcholinereceptor activity is partial agonism of mAChR M₁ activity. In a yetfurther aspect, the partial agonism of mAChR M₁ activity treats adisorder associated with mAChR M₁ activity in the mammal. In a stillfurther aspect, the mammal has been diagnosed with a need for treatmentof the disorder prior to the administering step. In an even furtheraspect, treatment further comprises the step of identifying a mammal inneed of treatment of the disorder.

In a further aspect, partial agonism of muscarinic acetylcholinereceptor activity in a mammal is associated with the treatment of aneurological and/or psychiatric disorder associated with mAChR M₁dysfunction. In a still further aspect, the disorder is Alzheimer'sdisease. In a yet further aspect, disorder is selected from psychosis,schizophrenia, conduct disorder, disruptive behavior disorder, bipolardisorder, psychotic episodes of anxiety, anxiety associated withpsychosis, psychotic mood disorders such as severe major depressivedisorder; mood disorders associated with psychotic disorders, acutemania, depression associated with bipolar disorder, mood disordersassociated with schizophrenia, behavioral manifestations of mentalretardation, conduct disorder, autistic disorder; movement disorders,Tourette's syndrome, akinetic-rigid syndrome, movement disordersassociated with Parkinson's disease, tardive dyskinesia, drug inducedand neurodegeneration based dyskinesias, attention deficit hyperactivitydisorder, cognitive disorders, dementias, and memory disorders. In aneven further aspect, the disorder is a neurological and/or psychiatricdisorder associated with M₁ receptor activity.

d. Modulating Muscarinic Acetylcholine Receptor Activity in a Mammal

In one aspect, the invention relates to a modulating muscarinicacetylcholine receptor activity in a mammal comprising the step ofadministering to the mammal an effective amount of least one compoundhaving a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered has a structurerepresented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound. In a stillfurther aspect, an effective amount is a therapeutically effectiveamount.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In a further aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, the compound exhibits modulation of mAChR M₁ withan EC₅₀ of less than about 10,000 nM. In a still further aspect, thecompound exhibits modulation of mAChR M₁ with an EC₅₀ of less than about5,000 nM. In an even further aspect, the compound exhibits modulation ofmAChR M₁ with an EC₅₀ of less than about 1,000 nM. In a further aspect,the compound exhibits modulation of mAChR M₁ with an EC₅₀ of less thanabout 500 nM. In a yet further aspect, the compound modulation of mAChRM₁ with an EC₅₀ of less than about 100 nM. In a further aspect, thecompound exhibits modulation of mAChR M₁ with an EC₅₀ of between fromabout 10,000 nM to about 1 nM. In a yet further aspect, the compoundexhibits modulation of mAChR M₁ with an EC₅₀ of between from about 1,000nM to about 1 nM. In a still further aspect, the compound exhibitsmodulation of mAChR M₁ with an EC₅₀ of between from about 100 nM toabout 1 nM. In an even further aspect, the compound exhibits modulationof mAChR M₁ with an EC₅₀ of between from about 10 nM to about 1 nM.

In one aspect, the mammal is a human. In a further aspect, the mammalhas been diagnosed with a need for modulation of muscarinicacetylcholine receptor activity prior to the administering step. In afurther aspect, the method further comprises the step of identifying amammal in need of modulating muscarinic acetylcholine receptor activity.In a further aspect, the modulation of muscarinic acetylcholine receptoractivity is associated with mAChR M₁ dysfunction.

In a further aspect, the modulation of muscarinic acetylcholine receptoractivity is modulation of mAChR M₁ activity. In a yet further aspect,the modulation of mAChR M₁ activity treats a disorder associated withmAChR M₁ activity in the mammal. In a still further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In an even further aspect, treatment furthercomprises the step of identifying a mammal in need of treatment of thedisorder.

In a further aspect, modulation of muscarinic acetylcholine receptoractivity in a mammal is associated with the treatment of a neurologicaland/or psychiatric disorder associated with mAChR M₁ dysfunction. In astill further aspect, the pharmaceutical composition is used to treat aneurological and/or psychiatric disorder. In a still further aspect, thedisorder is Alzheimer's disease. In a yet further aspect, disorder isselected from psychosis, schizophrenia, conduct disorder, disruptivebehavior disorder, bipolar disorder, psychotic episodes of anxiety,anxiety associated with psychosis, psychotic mood disorders such assevere major depressive disorder; mood disorders associated withpsychotic disorders, acute mania, depression associated with bipolardisorder, mood disorders associated with schizophrenia, behavioralmanifestations of mental retardation, conduct disorder, autisticdisorder; movement disorders, Tourette's syndrome, akinetic-rigidsyndrome, movement disorders associated with Parkinson's disease,tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

e. Modulating Muscarinic Acetylcholine Receptor Activity in Cells

In one aspect, the invention relates to a method for modulatingmuscarinic acetylcholine receptor activity in at least one cell,comprising the step of contacting the at least one cell with aneffective amount of least one compound having a structure represented bya formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the at least one compound has a structurerepresented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the compound administered is a disclosed compoundor a product of a disclosed method of making a compound. In a stillfurther aspect, an effective amount is a therapeutically effectiveamount.

In one aspect, modulating is increasing. In a further aspect, modulatingis potentiation. In a further aspect, modulating is partial agonism.

In a further aspect, an effective amount is a therapeutically effectiveamount.

In a further aspect, the compound exhibits modulation of mAChR M₁ withan EC₅₀ of less than about 10,000 nM. In a still further aspect, thecompound exhibits modulation of mAChR M₁ with an EC₅₀ of less than about5,000 nM. In an even further aspect, the compound exhibits modulation ofmAChR M₁ with an EC₅₀ of less than about 1,000 nM. In a further aspect,the compound exhibits modulation of mAChR M₁ with an EC₅₀ of less thanabout 500 nM. In a yet further aspect, the compound modulation of mAChRM₁ with an EC₅₀ of less than about 100 nM. In a further aspect, thecompound exhibits modulation of mAChR M₁ with an EC₅₀ of between fromabout 10,000 nM to about 1 nM. In a yet further aspect, the compoundexhibits modulation of mAChR M₁ with an EC₅₀ of between from about 1,000nM to about 1 nM. In a still further aspect, the compound exhibitsmodulation of mAChR M₁ with an EC₅₀ of between from about 100 nM toabout 1 nM. In an even further aspect, the compound exhibits modulationof mAChR M₁ with an EC₅₀ of between from about 10 nM to about 1 nM.

In one aspect, the cell is mammalian. In a further aspect, the cell ishuman. In a further aspect, the cell has been isolated from a mammalprior to the contacting step.

In a further aspect, contacting is via administration to a mammal. In afurther aspect, the mammal has been diagnosed with a need for modulationof muscarinic acetylcholine receptor activity prior to the administeringstep. In a further aspect, the method further comprises the step ofidentifying a mammal in need of modulating muscarinic acetylcholinereceptor activity. In a further aspect, the modulation of muscarinicacetylcholine receptor activity is associated with mAChR M₁ dysfunction.

In a further aspect, the modulation of muscarinic acetylcholine receptoractivity is modulation of mAChR M₁ activity. In a yet further aspect,the modulation of mAChR M₁ activity treats a disorder associated withmAChR M₁ activity in the mammal. In a still further aspect, the mammalhas been diagnosed with a need for treatment of the disorder prior tothe administering step. In an even further aspect, treatment furthercomprises the step of identifying a mammal in need of treatment of thedisorder.

In a further aspect, modulation of muscarinic acetylcholine receptoractivity in at least one cell is associated with the treatment of aneurological and/or psychiatric disorder associated with mAChR M₁dysfunction. In a still further aspect, the pharmaceutical compositionis used to treat a neurological and/or psychiatric disorder. In a stillfurther aspect, the disorder is Alzheimer's disease. In a yet furtheraspect, disorder is selected from psychosis, schizophrenia, conductdisorder, disruptive behavior disorder, bipolar disorder, psychoticepisodes of anxiety, anxiety associated with psychosis, psychotic mooddisorders such as severe major depressive disorder; mood disordersassociated with psychotic disorders, acute mania, depression associatedwith bipolar disorder, mood disorders associated with schizophrenia,behavioral manifestations of mental retardation, conduct disorder,autistic disorder; movement disorders, Tourette's syndrome,akinetic-rigid syndrome, movement disorders associated with Parkinson'sdisease, tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

2. Cotherapeutic Methods

The present invention is further directed to administration of aselective mAChR M₁ activator for improving treatment outcomes in thecontext of cognitive or behavioral therapy. That is, in one aspect, theinvention relates to a cotherapeutic method comprising the step ofadministering to a mammal an effective amount and dosage of at least onecompound having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the invention relates to a cotherapeutic methodcomprising the step of administering to a mammal an effective amount anddosage of at least one compound having a structure represented by aformula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, administration improves treatment outcomes in thecontext of cognitive or behavioral therapy. Administration in connectionwith cognitive or behavioral therapy can be continuous or intermittent.Administration need not be simultaneous with therapy and can be before,during, and/or after therapy. For example, cognitive or behavioraltherapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or afteradministration of the compound. As a further example, cognitive orbehavioral therapy can be provided within 1, 2, 3, or 4 weeks before orafter administration of the compound. As a still further example,cognitive or behavioral therapy can be provided before or afteradministration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 half-lives of the administered compound.

It is understood that the disclosed cotherapeutic methods can be used inconnection with the disclosed compounds, compositions, kits, and uses.

3. Manufacture of a Medicament

In one aspect, the invention relates methods for the manufacture of amedicament for modulating the activity mAChR M₁ (e.g., treatment of oneor more neurological and/or psychiatric disorder associated with mAChRM₁ dysfunction) in mammals (e.g., humans) comprising combining one ormore disclosed compounds, products, or compositions or apharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, with a pharmaceutically acceptable carrier.

It is understood that the disclosed methods can be performed with thedisclosed compounds, products, and pharmaceutical compositions. It isalso understood that the disclosed methods can be employed in connectionwith the disclosed methods of using.

In one aspect, the invention relates to a medicament comprising one ormore compounds having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the medicament comprises one or more compoundshaving a structure represented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

4. Use of Compounds

Also provided are the uses of the disclosed compounds and products. Inone aspect, the use relates to a treatment of a disorder in a mammal.Also disclosed is the use of a compound for mAChR M₁ receptoractivation. In one aspect, the use is characterized in that the mammalis a human. In one aspect, the use is characterized in that the disorderis a neurological and/or psychiatric disorder associated with muscarinicacetylcholine receptor dysfunction. In one aspect, the use relates topositive allosteric modulation of muscarinic acetylcholine receptoractivity in a mammal.

In one aspect, the invention relates to use of a compound having astructure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the invention relates to use of a compound having astructure represented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, a use relates to potentiation of muscarinicacetylcholine receptor activity in a mammal. In a further aspect, a userelates to partial agonism of muscarinic acetylcholine receptor activityin a mammal. In a further aspect, a use relates to enhancing cognitionin a mammal. In a further aspect, a use relates to modulating mAChR M₁activity in a mammal. In a still further aspect, a use relates tomodulating mAChR M₁ activity in a cell. In a yet further aspect, userelates to partial allosteric modulation of mAChR M₁. In an even furtheraspect, the mammal is a human.

In a further aspect, the pharmaceutical composition is used to treat aneurological and/or psychiatric disorder. In a still further aspect, thedisorder is Alzheimer's disease. In a yet further aspect, disorder isselected from psychosis, schizophrenia, conduct disorder, disruptivebehavior disorder, bipolar disorder, psychotic episodes of anxiety,anxiety associated with psychosis, psychotic mood disorders such assevere major depressive disorder; mood disorders associated withpsychotic disorders, acute mania, depression associated with bipolardisorder, mood disorders associated with schizophrenia, behavioralmanifestations of mental retardation, conduct disorder, autisticdisorder; movement disorders, Tourette's syndrome, akinetic-rigidsyndrome, movement disorders associated with Parkinson's disease,tardive dyskinesia, drug induced and neurodegeneration baseddyskinesias, attention deficit hyperactivity disorder, cognitivedisorders, dementias, and memory disorders. In an even further aspect,the disorder is a neurological and/or psychiatric disorder associatedwith M₁ receptor activity.

5. Kits

In one aspect, the invention relates to kits comprising at least onedisclosed compound or at least one product of a disclosed method and atleast one agent known to have M₁ receptor agonist activity.

Also disclosed are kits comprising at least one compound having astructure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 0, 1, or 2; wherein R²is selected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro,cyano, alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof, and one or more of: a) at least one agent known to increasemAChR M₁ activity; b) at least one agent known to decrease mAChR M₁activity; c) at least one agent known to treat a disorder associatedwith cholinergic activity; d) instructions for treating a disorderassociated with cholinergic activity; e) instructions for treating adisorder associated with M₁ receptor activity; or f) instructions foradministering the compound in connection with cognitive or behavioraltherapy.

In a further aspect, the kit comprises at least one compound having astructure represented by a formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

In a further aspect, the kit comprises a disclosed compound or a productof a disclosed method.

In a further aspect, the at least one compound and the at least oneagent are co-formulated. In a still further aspect, the at least onecompound and the at least one agent are co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is understood that the disclosed kits can be prepared from thedisclosed compounds, products, and pharmaceutical compositions. It isalso understood that the disclosed kits can be employed in connectionwith the disclosed methods of using.

6. Allosteric Activation of the Muscarinic Receptor

Also provided is a method for activation of the muscarinic receptor inat least one cell comprising the step of contacting the at least onecell with at least one disclosed compound in an amount effective toactivate muscarinic receptor activity in the at least one cell. In afurther aspect, provided is a method for activation of the muscarinicreceptor in a subject, the method comprising the step of administeringto the subject a therapeutically effective amount of at least onedisclosed compound, in a dosage and amount effective to activatemuscarinic receptor activity in the subject. In a further aspect, themethod can be applied to a subject, e.g., a mammal, including, forexample, a human.

7. Subjects

The subject of the herein disclosed methods can be a vertebrate, such asa mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subjectof the herein disclosed methods can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. A patient refers to a subject afflicted with adisease or disorder. The term “patient” includes human and veterinarysubjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with adisorder treatable by activation or modulation of the muscarinicreceptor and/or a need for activation or modulation of muscarinicreceptor activity prior to the administering step. In some aspects ofthe disclosed method, the subject has been diagnosed with anxiety or arelated disorder prior to the administering step. In some aspects of thedisclosed methods, the subject has been identified with a need fortreatment prior to the administering step. In some aspects of thedisclosed method, the subject has been identified with a disordertreatable by activation of the muscarinic receptor and/or or a need foractivation/modulation of muscarinic activity prior to the administeringstep. In some aspects of the disclosed method, the subject has beenidentified with anxiety or a related disorder prior to the administeringstep. In one aspect, a subject can be treated prophylactically with acompound or composition disclosed herein, as discussed herein elsewhere.

8. Non-Medical Uses

Also provided are the uses of the disclosed compounds and products aspharmacological tools in the development and standardization of in vivotest systems for the evaluation of the effects of modulators of mAChR M₁related activity in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeutic agentsof mAChR M₁. In a further aspect, the invention relates to uses of thedisclosed compounds and products as pharmacological tools in thedevelopment and standardization of in vitro test systems for theevaluation of the effects of modulators of mAChR M₁ related activity incell expressing mAChR M₁ as part of the search for new therapeuticagents of mAChR M₁, wherein the cells can be mammalian cell-lines, canbe primary cultures of cells from a tissue or organ, permanentcell-lines that express mAChR M₁, permanent cell-lines that express arecombinant form of mAChR M₁, and non-mammalian cells or cell-lineswhich express mAChR M₁, either as a native protein or recombinantprotein.

F. Experimental

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.

The following exemplary compounds of the invention were synthesized. TheExamples are provided herein to illustrate the invention, and should notbe construed as limiting the invention in any way. The Examples aretypically depicted in free base form, according to the IUPAC namingconvention.

1. General Methods

¹H NMR spectra were recorded either on a Bruker DPX-400 or on a BrukerAV-500 spectrometer with standard pulse sequences, operating at 400 MHzand 500 MHz respectively. Chemical shifts (δ) are reported in parts permillion (ppm) downfield from tetramethylsilane (TMS), which was used asinternal standard. Coupling constants (J-values) are expressed in Hzunits.

Microwave assisted reactions were performed in a single-mode reactor:Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currentlyBiotage).

Flash column chromatography was performed using ready-to-connectcartridges from: (a) ISCO, on irregular silica gel, particle size 15-40μm (normal layer disposable flash columns) on a Companion system fromISCO, Inc.; or, (b) Merck, on irregular silica gel, particle size 15-40μm (normal layer disposable flash columns) on an SPOT or LAFLASH systemfrom Armen Instrument.

Analytical HPLC was performed on an HP1100 with UV detection at 214 and254 nm along with ELSD detection and low resolution mass spectra usingan Agilent 1200 series 6130 mass spectrometer.

2. LC-MS Methods

The UPLC (Ultra Performance Liquid Chromatography) measurement wasperformed using an Acquity UPLC (Waters) system comprising a samplerorganizer, a binary pump with degasser, a four column's oven, adiode-array detector (DAD) and a column as specified below. Column flowwas used without split to the MS detector. The MS detector wasconfigured with an ESCI dual ionization source (electrospray combinedwith atmospheric pressure chemical ionization). Nitrogen was used as thenebulizer gas. The source temperature was maintained at 140° C. Dataacquisition was performed with MassLynx-Openlynx software. [M+H], meansthe protonated mass of the free base of the compound and where indicatedR_(t) means retention time (in minutes).

In the LC-MS analysis, reversed phase UPLC was carried out on a BEH-C18column (1.7 μm, 2.1×50 mm) from Waters, with a flow rate of 1.0 mL/min,at 50° C. without split to the MS detector. The gradient conditions usedare: 95% A (0.5 g/l ammonium acetate solution+5% acetonitrile), 5% B(acetonitrile), to 40% A, 60% B in 3.8 minutes, to 5% A, 95% B in 4.6minutes, kept till 5.0 minutes. Injection volume was 2.0 μl.Low-resolution mass spectra (single quadrupole, SQD detector) wereacquired by scanning from 100 to 1000 in 0.1 seconds using aninter-channel delay of 0.08 second. The capillary needle voltage was 3kV. The cone voltage was 25 V for positive ionization mode and 30 V fornegative ionization mode.

3. Preparation of Compounds

Examples 1 and 2 described below were prepared according to thefollowing scheme.

a. Example 12-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-n-(5-methylisoxazol-3-yl)acetamide

Step A.

Methyl 2-((4,6-difluoro-1H-indol-3-yl)thio)acetate. To a solution of4,6-difluoro-indole (1.00 g, 6.53 mmol) and methyl thioglycolate (584μL, 6.53 mmol) in methanol:water (25 mL:7.0 mL) was added iodine (1.65g, 6.53 mmol) and potassium iodide (1.09 g, 6.53 mmol). The reactionmixture was stirred at ambient temperature for 60 hours. Methanol wasremoved in vacuo and the aqueous layer diluted with a saturated solutionof sodium bicarbonate and extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, evaporated in vacuo and theresulting residue was purified on a silica gel column (0-100% ethylacetate:hexanes over 19 min) to afford the desired product (253 mg, 19%yield). LCMS>98% at 254 nm, RT=1.33 min, m/z=258 (M+1).

Step B.

2-((4,6-difluoro-1H-indol-3-yl)thio)acetic acid. Methyl2-((4,6-difluoro-1H-indol-3-yl)thio)acetate (253 mg, 0.98 mmol) fromStep A was dissolved in a mixture of tetrahydrofuran (8 mL) and 2.0 Maqueous LiOH (2 mL), then stirred vigorously at ambient temperature for30 minutes. Tetrahydrofuran was removed in vacuo, the aqueous layerneutralized with 1.2 N HCl and extracted with CH₂Cl₂. The organic layerwas dried over magnesium sulfate and removed in vacuo to produce an oilyresidue. After diluting the residue with diethylether and removing thesolvent in vacuo a solid formed which was the desired product (232 mg,0.95 mmol, 98% yield). LCMS>99% at 254 nm, RT=1.17 min, m/z=244 (M+1).

Step C.

2-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.2-((4,6-difluoro-1H-indol-3-yl)thio)acetic acid (160 mg, 0.66 mmol) fromStep B, 3-amino-5-methyl-isoxazole (130 mg, 1.32 mmol), PyClu (440 mg,1.32 mmol), and DIEA (289 μL, 1.65 mmol) were added to dichloroethane (5mL) and microwave irradiated at 110° C. for 30 minutes. The solvent wasremoved in vacuo and the remaining residue was dissolved in 5 mL (9:1,methanol:water) and oxone (641 mg, 1.0 mmol) was added and this mixturewas stirred at ambient temperature overnight. Water (5 mL) was added andthe mixture extracted with ethyl acetate (3×3 mL). The organics werecombined, dried over magnesium sulfate, and concentrated in vacuo togive an oily residue which was purified on a silica gel column (0-50%ethyl acetate:hexanes over 19 min) to yield the desired product (62.0mg, 0.174 mmol, 26% yield over 2 steps). LCMS>99% at 220 nm, RT=1.15min, m/z=356 (M+1).

Step D.

2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.In a 5 mL microwave vial,2-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide(62.0 mg, 0.174 mmol) from Step C was dissolved in DMF (3 mL) and cooledto 0° C. Sodium hydride (60% by weight, 8.0 mg, 0.35 mmol) was thenadded in one portion and the reaction mixture was vigorously stirred at0° C. for 15 minutes. 3-bromo-benzylbromide (44.0 mg, 0.174 mmol) wasadded in one portion and the reaction mixture was stirred while beingallowed to warm to ambient temperature over 3 hours. The reactionmixture was quenched with water (2 mL) and the solution was extractedwith ethyl acetate (3×4 mL). The organics were combined, dried overmagnesium sulfate, and concentrated in vacuo to give an oily residuewhich was purified on a silica gel column (0-50% ethyl acetate:hexanesover 19 min) to yield the title compound (45 mg, 0.09 mmol, 50% yield).LCMS>98% 220 nm, R_(T)=0.84 min, m/z=524 ([⁷⁹Br]m+1), 526 ([⁸¹Br]m+1).¹H NMR (400 MHz, DMSO_(D6)) 11.32 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H),7.52 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 2H), 6.52 (s, 1H),5.53 (s, 2H), 4.47 (s, 2H), 2.36 (s, 3H).

b. Example 22-((1-(3-(1H-pyrazol-4-yl)benzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide

Step E.

2-((1-(3-(1H-pyrazol-4-yl)benzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide.In a 5 mL microwave vial,2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methyl-isoxazol-3-yl)acetamide(20 mg, 0.38 mmol), prepared in Example 1, was dissolved in DMF (2 mL).PdCl₂(PPh₃)₂ (1.0 mg, 0.001 mmol), 1-Boc-pyrazole-4-boronic acid pinacolester (20 mg, 0.68 mmol), and 2 N aqueous sodium carbonate (1 mL) wereadded and stirred at 80° C. overnight. The reaction was cooled toambient temperature. Water (2 mL) was added and the mixture wasextracted with ethyl acetate (2×3 mL). The organics were combined, driedover magnesium sulfate and concentrated in vacuo to give an oily residuewhich was purified on a Gilson Prep HPLC system (5-95%acetonitrile:water (0.1% TFA) over 6 min) to afford the title compound(4.0 mg, 0.008 mmol, 21% yield) as a white solid. LCMS>98% 220 nm,R_(T)=0.79 min, m/z=512 (m+1). ¹H NMR (400 MHz, DMSO_(D6)) 12.97 (s,1H), 11.33 (s, 1H), 8.38 (s, 1H), 8.16, (s, 1H), 7.91 (s, 1H), 7.61 (s,1H), 7.49-7.55 (m, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.18 (d, J=10.8 Hz, 1H),7.00 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2.35(s, 3H).

c. Example 32-((1-(3-chlorobenzyl)-1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide

Example 3 was prepared according to the following scheme.

Step A.

Methyl 2-((1H-indol-3-yl)thio)acetate. To a solution of indole (3.00 g,25.6 mmol) and methyl thioglycolate (2.40 mL, 25.6 mmol) inmethanol:water (80 mL:20 mL) was added iodine (6.50 g, 25.6 mmol) andpotassium iodide (4.25 g, 25.6 mmol). The reaction mixture was stirredat ambient temperature for 60 hours. Methanol was removed in vacuo andthe aqueous layer diluted with a saturated solution of sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate, evaporated in vacuo and the resultingresidue was purified on a silica gel column (0-100% ethylacetate:hexanes over 33 min) to afford the desired product. LCMS>99% at254 nm, RT=1.29 min, m/z=222 (M+1).

Step B.

2-((1H-indol-3-yl)thio)acetic acid. Methyl2-((1H-indol-3-yl)thio)acetate from Step A was dissolved in a mixture oftetrahydrofuran (20 mL) and 2.0 M aqueous LiOH (15 mL), then stirredvigorously at ambient temperature for 30 min. Tetrahydrofuran wasremoved in vacuo, the aqueous layer neutralized with 1.2 N HCl andextracted with CH₂Cl₂. The organic layer was dried over magnesiumsulfate and the solvent was removed in vacuo to produce an oily residue.Upon diluting the residue in dichloromethane a solid formed which wasfiltered and dried to yield the desired product (2.00 grams, 9.65 mmol,38% yield over 2 steps). LCMS>99% at 254 nm, RT=1.02 min, m/z=208 (M+1).

Step C.

2-((1H-indol-3-yl)thio)-N-(5-methylisoxazol-3-yl)acetamide.2-((1H-indol-3-yl)thio)acetic acid (650 mg, 3.14 mmol) from Step B,3-amino-5-methyl-isoxazole (616 mg, 6.28 mmol), PyClu (2.00 g, 6.28mmol), and DIEA (1.36 mL, 7.85 mmol) were added to dichloroethane (25mL) and microwave irradiated at 110° C. for 20 minutes. The solvent wasremoved in vacuo and the remaining residue purified on a silica gelcolumn (0-70% ethyl acetate:hexanes over 33 min) to yield the desiredproduct (642 mg, 2.23 mmol, 71% yield). LCMS>99% at 214 nm, RT=1.23 min,m/z=288 (M+1).

Step D.

2-((1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide.2-((4,6-difluoro-1H-indol-3-yl)thio)-N-(5-methylisoxazol-3-yl)acetamide(100 mg, 0.348 mmol) from Step C was dissolved in hexafluoro-2-propanol(500 μL) and hydrogen peroxide (30% by weight, 88.0 μL, 0.696 mmol). Themixture was stirred at ambient temperature for 2 hours. The reaction wasquenched with saturated aqueous sodium sulfite (500 μL) and extractedwith ethyl acetate (3×1 mL). The organics were combined, dried overmagnesium sulfate, and concentrated in vacuo to give a residue which waspurified on a silica gel column (0-100% ethyl acetate:hexanes over 19min) to yield the desired product (79.0 mg, 0.174 mmol, 75% yield).LCMS>99% at 220 nm, RT=1.00 min, m/z=304 (M+1).

Step E.

2-((1-(3-chlorobenzyl)-1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide.In a 10 mL vial,2-((1H-indol-3-yl)sulfinyl)-N-(5-methylisoxazol-3-yl)acetamide (50.0 mg,0.165 mmol) from Step D was dissolved in DMF (5 mL) and cooled to 0° C.Sodium hydride (60% by weight, 13.0 mg, 0.330 mmol) was then added inone portion and the reaction mixture vigorously stirred at 0° C. for 15minutes. 3-chloro-benzylbromide (21.6 μL, 0.165 mmol) was added in oneportion and the reaction mixture was stirred while being allowed to warmto ambient temperature over 3 hours. The reaction mixture was quenchedwith water (2 mL) and the solution was extracted with ethyl acetate (3×2mL). The combined organics were dried over magnesium sulfate andconcentrated in vacuo to give an oily residue which was purified on asilica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield thetitle compound (24 mg, 0.056 mmol, 34% yield). LCMS>98% 220 nm,R_(T)=1.26 min, m/z=428 (m+1). ¹H NMR (400 MHz, DMSO_(D6)) 11.32 (s,1H), 8.19 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.38(s, 1H), 7.21-7.36 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 6.61 (s, 1H), 5.52(s, 2H), 4.58 (d, J=13.1 Hz, 1H), 4.14 (d, J=13.1 Hz, 1H), 2.38 (s, 3H).

d. Example 42-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(pyridin-2-yl)acetamide

Example 4 was prepared according to the following scheme.

Step A.

To a solution of 4,6-difluoro-indole (15.6 g, 0.102 mol) and methylthioglycolate (9.1 mL, 0.102 mol) in methanol:water (240 mL:60 mL) wasadded iodine (26.0 g, 0.102 mmol) and potassium iodide (17.0 g, 0.102mmol). The reaction mixture was stirred at ambient temperature for 60hours. Methanol was removed in vacuo and the aqueous layer diluted witha saturated solution of sodium bicarbonate and extracted with ethylacetate. The organic layer was dried over magnesium sulfate, evaporatedin vacuo and the resulting residue was purified on a silica gel column(0-100% ethyl acetate:hexanes over 48 min) to afford the desired product(20.1 g, 76% yield). ¹H NMR (400 MHz, DMSO_(D6)) 11.74 (s, 1H), 7.51 (d,J=2.4 Hz, 1H), 7.09 (dd, J=2.0, 9.6 Hz, 1H), 6.90-6.85 (m, 1H), 3.54 (s,3H), 3.51 (s, 2H).

Step B.

Methyl 2-((4,6-difluoro-1H-indol-3-yl)thio)acetate (3.5 g, 13.6 mmol)from Step A was dissolved in DMF (75 mL) and cooled to 0° C. Sodiumhydride (60% by weight, 600 mg, 15.0 mmol) was then added in threeportions and the reaction mixture vigorously stirred at 0° C. for 15minutes. 3-bromo-benzylbromide (3.75 g, 15.0 mmol) was added in oneportion and the reaction mixture was stirred while being allowed to warmto ambient temperature over 3 hours. The reaction mixture was quenchedwith water (2 mL) and the solution was extracted with ethyl acetate (3×4mL). The organics were combined, dried over magnesium sulfate, andconcentrated in vacuo to give an oily residue which was purified on asilica gel column (0-50% ethyl acetate:hexanes over 33 min) to yield thetitle compound (4.8 g, 11.3 mmol, 83% yield). LCMS>98% 254 nm,R_(T)=0.65 min, m/z=426 ([⁷⁹Br]m+1), 428 ([⁸¹Br]m+1). ¹H NMR (400 MHz,DMSO_(D6)) 7.76 (s, 1H), 7.51-7.48 (m, 2H), 7.38 (dd, J=2.0, 9.6 Hz,1H), 7.33 (t, J=7.6 Hz, 1H), 7.26 (d, J=2.0, 1H), 6.94 (dt, J=2.0, 11.6Hz, 1H), 5.40 (s, 2H), 3.53 (s, 2H), 3.52 (s, 3H).

Step C.

Methyl 2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)thio)acetate(810 mg, 1.9 mmol) from Step B was dissolved in 40 mL (9:1,methanol:water) and oxone (3.5 g, 5.7 mmol) was added and this mixturewas stirred at ambient temperature overnight. The mixture was filteredand concentrated in vacuo to yield a solid that was purified on a silicagel column (0-100% ethyl acetate:hexanes over 19 min) to yield thedesired product (767 mg, 1.67 mmol, 88% yield). LCMS>96% at 215 nm,RT=0.84 min, m/z=458 ([⁷⁹Br]m+1), 460 ([⁸¹Br]m+1). ¹H NMR (400 MHz,DMSO_(D6)) 8.44 (s, 1H), 7.56 (dd, J=1.6, 9.2 Hz, 1H), 7.53-7.50 (m,1H), 7.35-7.30 (m, 2H), 7.23-7.17 (m, 1H), 5.54 (s, 2H), 4.52 (s, 2H),3.55 (s, 3H).

Step D.

Methyl 2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)acetate(767 mg, 1.67 mmol) from Step C was dissolved in a mixture oftetrahydrofuran (20 mL) and 2.0 M aqueous LiOH (2.5 mL), then stirredvigorously at ambient temperature overnight. Tetrahydrofuran was removedin vacuo, the aqueous layer neutralized with 1.2 N HCl and extractedwith ethyl acetate. The organic layer was dried over magnesium sulfateand removed in vacuo to produce an oily residue that was purified on asilica gel column (0-100% ethyl acetate:hexanes over 19 min) to yieldthe desired product (296 mg, 0.66 mmol, 40% yield). LCMS>99% at 215 nm,RT=1.17 min, m/z=444 ([⁷⁹Br]m+1), 446 ([⁸¹Br]m+1). ¹H NMR (400 MHz,DMSO_(D6)) 8.27 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.46 (dd, J=2.0, 9.2Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15-7.10 (m,1H), 5.51 (s, 2H), 4.07 (s, 2H).

Step E.

2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)acetic acid(30 mg, 0.68 mmol) from Step D, 2-amino-pyridine (13 mg, 0.135 mmol),PyClu (45 mg, 0.135 mmol), and DIEA (29 μL, 0.169 mmol) were added todichloroethane (3 mL) and microwave irradiated at 110° C. for 30minutes. The solvent was removed in vacuo and the remaining residue waspurified on a Gilson reverse phase HPLC system with a Phenomenex, Luna50×21.2 mm, 5 uM C18 column (5%-95% water:acetonitrile over 6 min) toyield the desired product. LCMS>99% 215 nm, R_(T)=0.78 min, m/z=520([⁷⁹Br]m+1), 522 ([⁸¹Br]m+1). ¹H NMR (400 MHz, DMSO_(D6)) 10.89 (s, 1H),8.47 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.86 (t,J=8.4 Hz, 1H), 7.66 (s, 1H) 7.59 (d, J=8.4 Hz, 2H), 7.38-7.34 (m, 2H),5.61 (s, 2H), 4.64 (s, 2H), 2.16 (s, 3H). HRMS found 520.0142;calculated for C₂₂H₁₇N₃O₃SBrF₂, 520.0142.

e. Example 52-((1-(3-(1H-1,2,3-triazol-1-yl)benzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(pyridin-2-yl)acetamide

Example 5 was prepared according to the following scheme.

In a 5-mL conical microwave vial equipped with a stir bar,2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(pyridin-2-yl)acetamide(30 mg, 0.058 mmol, Example 7), sodium azide (10 mg, 0.15 mmol)), CuI(2.5 mg, 0.013 mmol), N,N′-dimethylaminediamine (2.0 mg, 0.23 mmol), andsodium ascorbate (5.0 mg, 0.025 mmol) were massed. The reagents weresuspended in ethanol/water (2:1, 5 mL) and the vial was sealed with acrimped cap. The reaction was heated to 120° C. with microwaveirradiation for 2 hours. The reaction was cooled to room temperature anddiluted with ethyl acetate (20 mL) and brine (20 mL). The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (2×20mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by flash columnchromatography eluting with hexanes/ethyl acetate to afford the puredesired compound,2-((1-(3-azidobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(pyridin-2-yl)acetamide.Into a dry round bottom flask equipped with a stir bar and septum,2-((1-(3-azidobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(pyridin-2-yl)acetamide(12 mg, 0.025 mmol), trimethylsilyl acetylene (6.0 mg, 0.61 mmol),copper sulfate (2.0 mg, 0.012 mmol), and sodium ascorbate (4.0 mg, 0.020mmol) were added. The flask was purged with argon, and the reagentsdissolved in MeOH/H₂O (2:1, 4 mL). The reaction was stirred at roomtemperature for 24 hours and monitored by LCMS. Upon completion, thereaction was diluted into dichloromethane (20 mL) and brine (20 mL). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified ona preparative Phenomenex Luna C18 column using 0.1% TFA inH₂O/acetonitrile as a mobile phase. The desired fractions were combinedand concentrated to afford the title compound. LCMS: R_(T)=0.624min, >99% @ 254 nm, >98% @ 215 nm; m/z (M+H)⁺=509. ¹H NMR (400 MHz,DMSO-d6, δ (ppm): (Note: two rotamers were observed for the desiredcompound in a 5:1 ratio; the integrations are reported such that for asingle proton the sum of both rotamers equals 1) 8.77 (s, 1H), 8.43-8.42(m, 1H), 8.38-8.31 (m, 1H), 8.15-8.13 (m, 0.2H (minor rotamer)),8.00-7.98 (m, 2H), 7.91-7.74 (m, 2.6H), 7.57-7.51 (m, 2H), 7.38 (m, 0.2H(minor rotamer)), 7.31-7.29 (m, 1H), 7.20-7.11 (m, 2H), 5.64 (s, 2H),4.89 (s, 0.4H (minor rotamer)), 4.56 (s, 1.6H (major rotamer)); HRMScalculated for C₂₄H₁₉N₆O₃SF₂ (M+H)⁺ m/z: 509.1207, measured: 509.1205.

4. Synthesis of Substituted Indole Analogs

Substituted indole analogs were synthesized using the general proceduresdescribed above. Compounds that were synthesized are given below inTable I with LC-MS data (M+H) and activity (potency and efficacy).Activity (potency and efficacy) was determined for compounds indicatedin the mAChR M₁ cell-based functional assay as described below.“Potency” is the EC₅₀ (nM), and “Efficacy” is defined as % Ach Max at 30μM (see assays below for further discussion).

TABLE I* No. Structure Name M + H Potency Efficacy  1

2-((1-benzyl-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N- (pyridin-2-yl)acetamide 442 990  59  2

2-((4,6-difluoro-1- (3-(pyridin-4- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N-(5- methylisoxazol-3- yl)acetamide 523 1200  66  3

2-((1-(3-(1H-1,2,3- triazol-1- yl)benzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl)-N- (5-methylisoxazol- 3-yl)acetamide 513 1500  72  4

2-((1-(3-(1H- pyrazol-4- yl)benzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl)-N- (5-methylisoxazol- 3-yl)acetamide 512 1850 102  5

2-((1-(3-(1H- pyrazol-4- yl)benzyl)-1H- indol-3- yl)sulfonyl)-N-(5-methylisoxazol-3- yl)acetamide 476 2190  90  6

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridin-2- yl)acetamide 520 2400  62  7

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridazin-3- yl)acetamide 521 2400  63  8

2-((4,6-difluoro-1- (3-(pyridin-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N-(5- methylisoxazol-3- yl)acetamide 523 2400  68  9

N- (benzo[d]oxazol- 2-yl)-2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl) acetamide 560 2500  44 10

2-((1-(3-(1H-1,2,3- triazol-1- yl)benzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl)-N- (pyridn-2- yl)acetamide 509 2600  67 11

2-((1-(3-(2- chloropyridin-3- yl)benzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 553 2700  43 12

2-((1-(3-(1-methyl- 1H-pyrazol-4- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N-(5- methylisoxazol-3- yl)acetamide 490 2755  95 13

2-((1-(3- azidobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridin-2- yl)acetamide 483 2800  53 14

2-((4,6-difluoro-1- (3-(pyridin-4- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 519 2900  55 15

2-((1-(2-fluoro-5- (1H-pyrazol-4- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N-(5- methylisoxazol-3- yl)acetamide 494 3070  96 16

2-((4,6-difluoro-1- (3-(6- methoxypyridin-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 549 3300  42 17

2-((1-(3-(3,5- dimethylisoxazol- 4-yl)benzyl)-4,6- difluoro-1H-indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 537 3400  42 18

2-((4,6-difluoro-1- (3-(2- methoxypyrimidin- 5-yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 550 3400  50 19

2-((4,6-difluoro-1- (3-(2- methoxypyrimidin- 5-yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 550 3400  50 20

2-((4,6-difluoro-1- (3-(2- fluoropyridin-4- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 537 3500  36 21

N- (benzo[d]isoxazol- 3-yl)-2-((1-(3- bromobenzyl)-4,6-difluoro-1H-indol- 3-yl)sulfonyl) acetamide 560 3700  72 22

2-((1-(3- bromobenzyl)-1H- indol-3- yl)sulfonyl)-N-(5- methylisoxazol-3-yl)acetamide 488 3790  91 23

2-((1-(2-fluoro-3- (1H-pyrazol-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N-(5- methylisoxazol-3- yl)acetamide 494 4400 103 24

2-((4,6-difluoro-1- (3-(2- fluoropyridin-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 537 4400  38 25

2-((4,6-difluoro-1- (3-(pyridin-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 519 4600  57 26

2-((1-(3-chloro-2- fluorobenzyl)-1H- indol-3- yl)sulfonyl)-N-(5-methylisoxazol-3- yl)acetamide 462 5100  56 27

2-((4,6-difluoro-1- (3-(6- fluoropyridin-3- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 537 5200  42 28

2-((1-(3- fluorobenzyl)-1H- indol-3- yl)sulfonyl)-N-(5-methylisoxazol-3- yl)acetamide 428 5220  96 29

2-((1-(3- chlorobenzyl)-1H- indol-3- yl)sulfinyl)-N-(5-methylisoxazol-3- yl)acetamide 428 5230  93 30

2-((1-(3- bromobenzyl)-4,6- 3-yl)sulfonyl)-N- (5-methylisoxazol-3-yl)acetamide 524 5370 103 31

2-((1-(3- aminobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridin-2- yl)acetamide 457 5600  69 32

2-((1-(3- chlorobenzyl)-1H- indol-3- yl)sulfonyl)-N-(5-methylisoxazol-3- yl)acetamide 444 5820  96 33

2-((1-(3- methoxybenzyl)- 1H-indol-3- yl)sulfonyl)-N-(5-methylisoxazol-3- yl)acetamide 440 6540  79 *EC₅₀, nM; % ACh maximum at30 μM.

TABLE II** No. Structure Name M + H Potency Efficacy 34

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(oxetan-3- yl)acetamide 499 >10,000 43 35

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridin-3- yl)acetamide 520 >10,000 42 36

2-((4,6-difluoro-1- (3-(pyrimidin-5- yl)benzyl)-1H- indol-3-yl)sulfonyl)-N- (pyridin-2- yl)acetamide 520 >10,000 45 37

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyrimidin-5-yl) acetamide 521 >10,000 48 38

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(thiazol-5-yl) acetamide 525 >10,000 49 39

2-((1-(3- bromobenzyl)-4,6- difluoro-1H-indol- 3-yl)sulfonyl)-N-(pyridin-2-ylmethyl) acetamide 534 >10,000 34 40

2-((4,6-difluoro-1- (3-(2- methoxypyridin-3- yl)benzyl)-1H-indol-3-yl)sulfonyl)-N- (pyridin-2-yl)acetamide 549 >10,000 37 41

2-(1H-indol-3- ylsulfanyl)-N-(5- methyl-1,2-oxazol- 3-yl)acetamide288 >10000 n.d. 42

2-({1-[(2- chlorophenyl) methyl]-1H-indol- 3-yl}sulfanyl)- N-(5-methyl-1,2-oxazol- 3-yl)acetamide 412 >10000 n.d. 43

2-{1-[(2- fluorophenyl) methyl]-1H-indole- 3-sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 428 >10000 n.d. 44

2-{1-[(6- fluoropyridin-3- yl)methyl]-1H- indole-3-sulfonyl}-N-(5-methyl-1,2- oxazol-3- yl)acetamide 429 >10000 n.d. 45

2-{1-[(3- cyanophenyl) methyl]-1H-indole- 3-sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 435 >10000 n.d. 46

2-{1-[(4- methoxyphenyl) methyl]-1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 400 >10000 n.d. 47

2-{1-[(2- methoxyphenyl) methyl]-1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 440 >10000 n.d. 48

2-{1-[(4- chlorophenyl)methyl]- 1H-indole-3-sulfonyl}- N-(5-methyl-1,2-oxazol-3-yl) acetamide 444 >10000 n.d. 49

2-{1-[(2,4- difluorophenyl)methyl]- 1H-indole-3-sulfonyl}-N-(5-methyl-1,2- oxazol-3-yl)acetamide 446 >10000 n.d. 50

2-[1-(2H-1,3- benzodioxol-5- ylmethyl)-1H- indole-3-sulfonyl]-N-(5-methyl-1,2- oxazol-3- yl)acetamide 454 >10000 n.d. 51

2-({1-[(3- bromphenyl)methyl]- 1H-indol-3-yl} sulfanyl)-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 456 >10000 n.d. 52

2-{1-[(3-chloro-4- fluorophenyl)methyl]- 1H-indole-3-sulfonyl}-N-(5-methyl-1,2- oxazol-3-yl) acetamide 462 >10000 n.d. 53

N-(5-methyl-1,2- oxazol-3-yl)-2-(1- {[4-(trifluoromethyl)phenyl]methyl}-1H- indole-3- sulfonyl)acetamide 478 >10000 n.d. 54

N-(5-methyl-1,2- oxazol-3-yl)-2-(1- {[3-(trifluoromethyl)phenyl]methyl}-1H- indole-3- sulfonyl)acetamide 478 >10000 n.d. 55

2-{1-[(3,4- dichlorophenyl) methyl]-1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 478 >10000 n.d. 56

N-(5-methyl-1,2- oxazol-3-yl)-2-{1- [(3-phenylphenyl)methyl]-1H-indole-3- sulfonyl}acetamide 486 >10000 n.d. 57

N-(5-methyl-1,2- oxazol-3-yl)-2-(1- {[4- (trifluoromethoxy)phenyl]methyl}- 1H-indole-3- sulfonyl)acetamide 494 >10000 n.d. 58

2-(1-{[4-fluoro-3- (1H-pyrazol-3- yl)phenyl]methyl}- 1H-indole-3-sulfonyl)-N-(5- methyl-1,2-oxazol- 3-yl)acetamide 494 >10000 n.d. 59

2-{1-[(5-bromo-2- fluorophenyl)methyl]- 1H-indole-3- sulfonyl}-N-phenylacetamide 501 >10000 n.d. 60

2-{1-[(4-bromo-2- fluorophenyl)methyl]- 1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 506 >10000 n.d. 61

2-{1-[(3-bromo-4- fluorophenyl)methyl]- 1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 506 >10000 n.d. 62

2-{1-[(3-bromo-2- fluorophenyl)methyl]- 1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 506 >10000 n.d. 63

2-{1-[(5-bromo-2- fluorophenyl)methyl]- 1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)propanamide 520 >10000 n.d. 64

2-(1-{[3-(6- chloropyridin-3- yl)phenyl]methyl}- 1H-indole-3-sulfonyl)-N-(5- methyl-1,2-oxazol- 3-yl)acetamide 521 >10000 n.d. 65

N-(5-methyl-1,2- oxazol-3-yl)-2-[1- ({3-[1-(2- methylpropyl)-1H-pyrazol-4- yl]phenyl}methyl)- 1H-indole-3- sulfonyl]acetamide 532 >10000n.d. 66

3-(2- fluorophenyl)-2- {1-[(2- fluorophenyl)methyl]-1H-indole-3-sulfonyl}- N-(5-methyl-1,2- oxazol-3-yl) propanamide536 >10000 n.d. 67

N-(5-methyl-1,2- oxazol-3-yl)-2-[1- ({3-[6-(pyrrolidin- 1-yl)pyridin-3-yl]phenyl}methyl)- 1H-indole-3- sulfonyl]acetamide 556 >10000 n.d. 68

2-{1-[(3,5- dibromophenyl) methyl]-1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)acetamide 566 >10000 n.d. 69

3-(3- chlorophenyl)-2- {1-[(3- chlorophenyl) methyl]-1H-indole-3-sulfonyl}-N-(5- methyl-1,2-oxazol- 3-yl)propanamide 568 >10000 n.d. 70

N-(5-methyl-1,2- oxazol-3-yl)-2-[1- ({3-[6-(piperazin- 1-yl)pyridin-3-yl]phenyl}methyl)- 1H-indole-3- sulfonyl]acetamide 571 >10000 n.d. 71

3-(2,4- difluorophenyl)-2- {1-[(2,4- difluorophenyl)methyl]-1H-indole-3- sulfonyl}-N-(5- methyl-1,2-oxazol- 3-yl)propanamide572 >10000 n.d. 72

N-(5-methyl-1,2- oxazol-3-yl)-2-[1- ({3-[6-(morpholin- 4-yl)pyridin-3-yl]phenyl}methyl)- 1H-indole-3- sulfonyl]acetamide 572 >10000 n.d. 73

2-{1-[(3,5- dibromophenyl) methyl]-1H-indole-3- sulfonyl}-N-(5-methyl-1,2-oxazol- 3-yl)propanamide 580 >10000 n.d. 74

N-(5-methyl-1,2- oxazol-3-yl)-3-[4- (trifluoromethoxy) phenyl]-2-(1-{[4-(trifluoromethoxy) phenyl]methyl}- 1H-indole-3- sulfonyl)propanamide668 >10000 n.d. **EC₅₀, nM; % ACh maximum at 30 μM.

The selectivity of the disclosed compounds for mAChR M₁ compared tomAChR M₂, M₃, M₄, and M₅ was determined using the cell-based functionalassay described below using the appropriate cell-lines (prepared asdescribed below). The EC₅₀ for each of mAChR M₂, M₃, M₄, and M₅ wasgreater than at least 30 μM for representative compounds (i.e., therewas no receptor response up to a concentration of about 30 μM, the upperlimit of compound used in the assay).

5. Cell Lines Expressing Muscarinic Acetylcholine Receptors

Chinese hamster ovary (CHO-K1) cells stably expressing rat (r)M₁ werepurchased from the American Type Culture Collection and culturedaccording to their indicated protocol. CHO cells stably expressing human(h)M₂, hM₃, and hM₅ were described previously (Levey et al., 1991); hM₁and hM₄ cDNAs were purchased from Missouri S&T cDNA Resource; rM₄ cDNAwas provided by T. I. Bonner (National Institutes of Health, Bethesda,Md.). rM₂ and rM₃ were cloned from a rat brain cDNA library and sequenceverified. hM₁, rM₂, rM₃, hM₄, and rM₄ cDNAs were used to stablytransfect CHO-K1 cells purchased from the American Type CultureCollection using Lipofectamine-2000. To make stable rM₂, hM₂, rM3, hM₄,and rM₄ cell lines for use in calcium mobilization assays, these cellsalso were stably transfected with a chimeric G-protein (G_(qi5))(provided by B. R. Conklin, University of California, San Francisco)using Lipofectamine 2000. rM₁, hM₁, rM₃, hM₃, rM₅, and hM₅ cells weregrown in Ham's F-12 medium containing 10% heat-inactivated fetal bovineserum (FBS), 20 mM HEPES, and 50 μg/mL G418 sulfate. rM2-G_(qi5),hM₂-G_(qi5), and hM₄-G_(qi5) cells were grown in the same medium alsocontaining 500 μg/mL Hygromycin B. Stable rM₄-G_(qi5) cells were grownin DMEM containing 10% heat-inactivated FBS, 20 mM HEPES, 400 μg/mL G418sulfate, and 500 μg/mL Hygromycin B.

6. Cell-Based Functional Assay of Muscarinic Acetylcholine ReceptorActivity

For high throughput measurement of agonist-evoked increases inintracellular calcium, CHO-K1 cells stably expressing muscarinicreceptors were plated in growth medium lacking G418 and hygromycin at15,000 cells/20 μL/well in Greiner 384-well black-walled, tissue culture(TC)-treated, clear-bottom plates (VWR). Cells were incubated overnightat 37° C. and 5% CO₂. The next day, cells were washed using an ELX 405(BioTek) with four washes (80 μL) of assay buffer then aspirated to 20μL. Next, 20 μL of 16 μM Fluo-4/acetoxymethyl ester (Invitrogen,Carlsbad, Calif.) prepared as a 2.3 mM stock in DMSO and mixed in a 1:1ratio with 10% (w/v) Pluronic F-127 and diluted in assay buffer wasadded to the wells and the cell plates were incubated for 50 min at 37°C. and 5% CO₂. Dye was removed by washing with the ELX 405 (four 80 μLwashes of assay buffer) then aspirated to 20 μL. Compound master plateswere formatted in an 11 point CRC format (1:3 dilutions) in 100% DMSOwith a starting concentration of 10 mM using the BRAVO liquid handler(Agilent). Test compound CRCs were then transferred to daughter plates(240 nL) using the Echo acoustic plate reformatter (Labcyte, Sunnyvale,Calif.) and then diluted into assay buffer (40 μL) to a 2× stock using aThermo Fisher Combi (Thermo Fisher Scientific, Waltham, Mass.).

Calcium flux was measured using the Functional Drug Screening System(FDSS) 6000 (Hamamatsu Corporation, Tokyo, Japan) as an increase in thefluorescent static ratio. Compounds were applied to cells (20 μL, 2×)using the automated system of the FDSS 6000 at 4 s into the 300 sprotocol and the data were collected at 1 Hz. At 144 s into the 300 sprotocol, 10 μL of an EC₂₀ concentration of the muscarinic receptoragonist acetylcholine was added (5×), followed by the addition of 12 μLan EC₈₀ concentration of acetylcholine at the 230 s time point (5×).Agonist activity was analyzed as a concentration-dependent increase incalcium mobilization upon compound addition. Positive allostericmodulator activity was analyzed as a concentration-dependent increase inthe EC₂₀ acetylcholine response. Antagonist activity was analyzed as aconcentration-dependent decrease in the EC₈₀ acetylcholine response.Concentration-response curves were generated using a four-parameterlogistical equation in XLfit curve fitting software (IDBS, Bridgewater,N.J.) for Excel (Microsoft, Redmond, Wash.) or Prism (GraphPad Software,Inc., San Diego, Calif.).

The above described assay was also operated in a second mode where anappropriate fixed concentration of the present compounds were added tothe cells after establishment of a fluorescence baseline for about 3seconds, and the response in cells was measured. 140 s later theappropriate concentration of agonist was added and readings taken for anadditional 106 s. Data were reduced as described above and the EC₅₀values for the agonist in the presence of test compound were determinedby nonlinear curve fitting. A decrease in the EC₅₀ value of the agonistwith increasing concentrations of the present compounds (a leftwardshift of the agonist concentration-response curve) is an indication ofthe degree of muscarinic positive allosteric modulation at a givenconcentration of the present compound. An increase in the EC₅₀ value ofthe agonist with increasing concentrations of the present compounds (arightward shift of the agonist concentration response curve) is anindication of the degree of muscarinic antagonism at a givenconcentration of the present compound. The second mode also indicateswhether the present compounds also affect the maximum response of themuscarinic receptor to agonists.

The calcium mobilization assay was also used to determine “efficacy”. Inthe context of the assays carried out for the data in Table I,“efficacy” (% ACh at 30 μM) is defined as the maximal response in thecalcium flux as determined by the sigmoidal curve fit of theconcentration response curve, or in the absence of an acceptable curvefit, the response recorded at 30 μM test compound, stated as apercentage of the response elicited by a concentration of Ach thatinduces approximately 80% of a maximal (i.e. saturating) ACh response.

7. Prophetic In Vivo Effects

Generally clinically relevant antipsychotic agents (both typical andatypical) display efficacy in preclinical behavior challenge models. Invivo effects of the disclosed compounds described in the precedingexamples and in the specification are expected to be shown in variousanimal behavioural challenge models known to the skilled person, such asamphetamine-induced or phencyclidine (PCP)-induced hyperlocomotion, andother models, such as NMDA receptor antagonist MK-801-induced locomotoractivity. These models are typically conducted in rodent, such as rat ormouse, but may be conducted in other animal species as is convenient tothe study goals. Compounds, products, and compositions disclosed hereinare expected to show in vivo effects in various animal behaviouralchallenge models known to the skilled person, such asamphetamine-induced or phencyclidine (PCP)-induced hyperlocomotion inrodent, and other models, such as NMDA receptor antagonistMK-801-induced locomotor activity. These models are typically conductedin rodent, such as rat or mouse, but may be conducted in other animalspecies as is convenient to the study goals.

For example, compounds having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorph thereofare expected to show such in vivo effects.

Alternatively, for example, compounds having a structure represented bya formula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof are expected to show such in vivo effects.

One suitable method to assess the anti-psychotic effect of the disclosedcompounds will be described herein, i.e. the amphetamine-inducedhyperlocomotor activity assay. Other models known to one skilled in theart as described above can also be used to determine the anti-psychotic,cognitive, or neuropathic pharmacological effects of the disclosedcompounds.

The amphetamine-induced hyperlocomotor activity studies are conductedusing male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc.,Indianapolis, Ind.) weighing 270 to 300 g. Subject animals are housed inpairs in a large colony room under a 12-h light/12-h dark cycle (lightson at 6:00 AM) with food and water provided ad libitum. Test sessionsare performed between 6:00 AM and 6:00 PM. Dose groups consisted of 8 to16 rats per dose group. Doses of test compound are injected in a 1.0ml/kg volume. Each test compound is prepared in a suitable vehicleformulation, e.g. the test compound can be dissolved in 10% Tween 80 anddouble deionized water with the pH adjusted to approximately 7.0 using 1N NaOH.

The studies are conducted using a SmartFrame Open Field System (KinderScientific., San Diego, Calif.) equipped with 32 horizontal (x- andy-axes) infrared photobeams located 1 cm above the floor of the chamber.Changes in ambulation or locomotor activity were measured as the numberof total photobeam breaks, expressed in 5-min intervals, and wererecorded with a Pentium I computer equipped with the Motor MonitorSystem software (Kinder Scientific).

Rats are placed in the open-field chambers for a 30-min habituationinterval (data not shown), followed by a pretreatment for 30 minuteswith vehicle or a suitable dose of test compound administered by i.p.injection or alternatively by oral gavage dose. Suitable doses for usein this study are from about 1 mg/kg to about 100 mg/kg. Next, all ratsreceive an injection of 1 mg/kg s.c. amphetamine, and locomotor activityis measured for an additional 60 min. Data are analyzed by a one-wayANOVA with comparison with the vehicle+amphetamine control group usingDunnett's test. Calculations are performed using JMP version 5.1.2 (SASInstitute Inc., Cary, N.C.) statistical software.

The effects of a test compound on motor performance are evaluated usinga rotorod (Columbus Instruments, Columbus, Ohio). All rats are given aninitial training trial of 120 s, followed by two additional trainingtrials of 85 s, approximately 10 min apart, using a rotorod (7.5 cm indiameter) rotating at a constant speed of 20 revolutions/min. Afterinitial training trials, a baseline trial of 85 s is conducted, and anyrats that did not reach the 85-s criteria were excluded from the study.Rats are then pretreated for 30 min i.p. or oral gavage, as appropriate,with vehicle or dose of test compound, e.g. about 30, 50, or 100 mg/kg,and then the time each animal remains on the rotorod is recorded;animals not falling off of the rotorod are given a maximal score of 85s. Data are analyzed by a one-way ANOVA, with comparison to the vehiclecontrol group using Dunnett's test. Calculations are performed using JMPversion 5.1.2 (SAS Institute Inc.) statistical software.

8. Prophetic Pharmaceutical Composition Examples

“Active ingredient” as used throughout these examples, relates to one ormore compounds having a structure represented by a formula (I):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein A² isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or apharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

“Active ingredient” as used throughout these examples, alternativelyrelates to one or more compounds having a structure represented by aformula (II):

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R^(5a),R^(5c), and R^(5e) are independently selected from H, Cl, Br, F,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted alkoxy, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;wherein R^(5b) and R^(5d) are independently selected from H, Cl, Br,azido, amino, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; provided that at least one of R^(5b) and R^(5d)is not hydrogen; provided that the compound is not2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphthereof.

The following examples of the formulation of the compounds of thepresent invention in tablets, suspension, injectables and ointments areprophetic. Typical examples of recipes for the formulation of theinvention are as given below.

a. Tablets

A tablet can be prepared as follows:

Component Amount Active ingredient 5 to 50 mg Di-calcium phosphate 20 mgLactose 30 mg Talcum 10 mg Magnesium stearate 5 Potato starch add tomake total weight 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

b. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

c. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

d. Ointment

An ointment can be prepared as follows:

Component Amount Active ingredient 5 to 1000 mg Stearyl alcohol 3 gLanoline 5 g White petroleum 15 g Water add to make total weight 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otheraspects of the invention will be apparent to those skilled in the artfrom consideration of the specification and practice of the inventiondisclosed herein. It is intended that the specification and examples beconsidered as exemplary only, with a true scope and spirit of theinvention being indicated by the following claims.

What is claimed is:
 1. A compound represented by a formula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one of R^(1a)or R^(1c) is F; wherein n is 0, 1, or 2; wherein R² is selected fromhydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; wherein R³ comprises twosubstituents independently selected from hydrogen, halogen, hydroxyl,thiol, sulfo, nitro, cyano, alkoxyl, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; wherein R⁴ is selected from hydrogen, ahydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and wherein A²is selected from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl.
 2. The compoundof claim 1, wherein each of R^(1a) and R^(1c) is F.
 3. The compound ofclaim 1, wherein each of R^(1b) and R^(1d) is hydrogen.
 4. The compoundof claim 1, wherein R² is hydrogen.
 5. The compound of claim 1, whereinn is
 2. 6. The compound of claim 1, wherein A¹ is selected fromoptionally substituted pyridine, optionally substituted pyrimidine,optionally substituted furan, optionally substituted thiophene,optionally substituted pyrrole, optionally substituted isoxazole,optionally substituted isothiazole, optionally substituted pyrazole,optionally substituted oxazole, optionally substituted thiazole, andoptionally substituted imidazole.
 7. The compound of claim 1, wherein A¹is optionally substituted oxazole.
 8. The compound of claim 1, whereinA² is selected from optionally substituted aryl and optionallysubstituted heteroaryl.
 9. The compound of claim 1, represented by aformula:

wherein R^(5a), R^(5c), and R^(5e) are independently selected from H,Cl, Br, F, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkoxy, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and wherein R^(5b) and R^(5d) are independentlyselected from H, Cl, Br, azido, amino, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted alkoxy,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; provided that at least one ofR^(5b) and R^(5d) is not hydrogen.
 10. The compound of claim 9, whereineach of R^(1a) and R^(1c) is F.
 11. The compound of claim 9, whereineach of R^(1b) and R^(1d) is hydrogen.
 12. A compound represented by aformula:

wherein each R^(1a)-R^(1d) is independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein n is 1 or 2; wherein R² isselected from hydrogen, halogen, hydroxyl, thiol, sulfo, nitro, cyano,alkoxyl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; wherein R³comprises two substituents independently selected from hydrogen,halogen, hydroxyl, thiol, sulfo, nitro, cyano, alkoxyl, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; wherein R⁴ is selected from hydrogen,a hydrolysable residue, and optionally substituted alkyl; wherein A¹ isselected from pyridinyl, pyridinylmethyl, pyridazinyl, pyrimidinyl,5-methylisoxazol-3-yl, benzoxazolyl, benzoisoxazolyl, oxetanyl, andthiazolyl, and A¹ is substituted with 0-2 groups selected from halogen,cyano, C1-C4 alkyl, C1-C4 alkoxyl, and C1-C4 haloalkyl; wherein eachR^(5a)-R^(5e) is independently selected from hydrogen, fluoro, chloro,bromo, iodo, azido, amino, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkoxy, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; provided that at least one ofR^(5a)-R^(5e) is selected from optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,and optionally substituted heteroaryl; or at least two of R^(5a)-R^(5e)are independently selected from fluoro, chloro, bromo, iodo, azido,amino, alkyl, and alkoxy.
 13. The compound of claim 12, wherein n is 2.14. The compound of claim 12, wherein at least one of R^(5a)-R^(5e) isselected from optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl.
 15. The compound of claim 12, wherein eachR^(1a)-R^(1d) is hydrogen.
 16. The compound of claim 12, wherein atleast one of R^(1a) or R^(1c) is F.